74 results on '"Camisaschi, C"'
Search Results
2. Immunological characterization of a long-lasting response in a patient with metastatic triple-negative breast cancer treated with PD-1 and LAG-3 blockade
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Rivoltini, L, Camisaschi, C, Fucà, G, Paolini, B, Vergani, B, Beretta, V, Damian, S, Duca, M, Cresta, S, Magni, M, Leone, B, Castelli, C, de Braud, F, De Santis, F, Di Nicola, M, Rivoltini, Licia, Camisaschi, Chiara, Fucà, Giovanni, Paolini, Biagio, Vergani, Barbara, Beretta, Valeria, Damian, Silvia, Duca, Matteo, Cresta, Sara, Magni, Michele, Leone, Biagio Eugenio, Castelli, Chiara, de Braud, Filippo, De Santis, Francesca, Di Nicola, Massimo, Rivoltini, L, Camisaschi, C, Fucà, G, Paolini, B, Vergani, B, Beretta, V, Damian, S, Duca, M, Cresta, S, Magni, M, Leone, B, Castelli, C, de Braud, F, De Santis, F, Di Nicola, M, Rivoltini, Licia, Camisaschi, Chiara, Fucà, Giovanni, Paolini, Biagio, Vergani, Barbara, Beretta, Valeria, Damian, Silvia, Duca, Matteo, Cresta, Sara, Magni, Michele, Leone, Biagio Eugenio, Castelli, Chiara, de Braud, Filippo, De Santis, Francesca, and Di Nicola, Massimo
- Abstract
In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade. Trial registration: NCT02460224. Registered 02/06/2015.
- Published
- 2024
3. Reduction of Staphylococcus epidermidis in the mammary tumor microbiota induces antitumor immunity and decreases breast cancer aggressiveness
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Bernardo, G, Le Noci, V, Ottaviano, E, De Cecco, L, Camisaschi, C, Guglielmetti, S, Di Modica, M, Gargari, G, Bianchi, F, Indino, S, Sartori, P, Borghi, E, Sommariva, M, Tagliabue, E, Triulzi, T, Sfondrini, L, Bernardo, G, Le Noci, V, Ottaviano, E, De Cecco, L, Camisaschi, C, Guglielmetti, S, Di Modica, M, Gargari, G, Bianchi, F, Indino, S, Sartori, P, Borghi, E, Sommariva, M, Tagliabue, E, Triulzi, T, and Sfondrini, L
- Abstract
The mammary gland hosts a microbiota, which differs between malignant versus normal tissue. We found that aerosolized antibiotics decrease murine mammary tumor growth and strongly limit lung metastasis. Oral absorbable antibiotics also reduced mammary tumors. In ampicillin-treated nodules, the immune microenvironment consisted of an M1 profile and improved T cell/macrophage infiltration. In these tumors, we noted an under-representation of microbial recognition and complement pathways, supported by TLR2/TLR7 protein and C3-fragment deposition reduction. By 16S rRNA gene profiling, we observed increased Staphylococcus levels in untreated tumors, among which we isolated Staphylococcus epidermidis, which had potent inflammatory activity and increased Tregs. Conversely, oral ampicillin lowered Staphylococcus epidermidis in mammary tumors and expanded bacteria promoting an M1 phenotype and reducing MDSCs and tumor growth. Ampicillin/paclitaxel combination improved the chemotherapeutic efficacy. Notably, an Amp-like signature, based on genes differentially expressed in murine tumors, identified breast cancer patients with better prognosis and high immune infiltration that correlated with a bacteria response signature. This study highlights the significant influence of mammary tumor microbiota on local immune status and the relevance of its treatment with antibiotics, in combination with breast cancer therapies.
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- 2023
4. 84P Profiling of lipid-loaded macrophages in melanoma
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Pandini, M., Iovino, M., Marelli, G., Morina, N., Carvetta, M., Portale, F., De Simone, G., Camisaschi, C., Basso, G., Giuliano, D., and Di Mitri, D.
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- 2023
- Full Text
- View/download PDF
5. Phenotypical and molecular landscape of B lymphocytes in patients with Intrahepatic Cholangiocarcinoma
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Milardi, G., primary, Franceschini, B., additional, Camisaschi, C., additional, Costa, G., additional, Soldani, C., additional, Uva, P., additional, Cassani, B., additional, and Lleo, A., additional
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- 2023
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6. Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg)
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Donini, M., Buti, S., Lazzarelli, S., Bozzetti, R., Rivoltini, L., Camisaschi, C., Castelli, C., Bearz, A., Simonelli, C., Lo Re, G., Mattioli, R., Caminiti, C., Passalacqua, R., and GOIRC (Italian Oncology Group for Clinical Research)
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- 2015
- Full Text
- View/download PDF
7. Modulation of Pulmonary Microbiota by Antibiotic or Probiotic Aerosol Therapy: A Strategy to Promote Immunosurveillance against Lung Metastases
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Le Noci, V, Guglielmetti, S, Arioli, S, Camisaschi, C, Bianchi, F, Sommariva, M, Storti, C, Triulzi, T, Castelli, C, Balsari, A, Tagliabue, E, Sfondrini, L, Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, Storti C, Triulzi T, Castelli C, Balsari A, Tagliabue E, Sfondrini L, Le Noci, V, Guglielmetti, S, Arioli, S, Camisaschi, C, Bianchi, F, Sommariva, M, Storti, C, Triulzi, T, Castelli, C, Balsari, A, Tagliabue, E, Sfondrini, L, Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, Storti C, Triulzi T, Castelli C, Balsari A, Tagliabue E, and Sfondrini L
- Abstract
Pulmonary immunological tolerance to inhaled particulates might create a permissive milieu for lung metastasis. Lung microbiota contribute to pulmonary tolerance; here, we explored whether its manipulation via antibiotic or probiotic aerosolization favors immune response against melanoma metastasis. In lungs of vancomycin/neomycin-aerosolized mice, a decrease in bacterial load was associated with reduced regulatory T cells and enhanced T cell and NK cell activation that paralleled a significant reduction of melanoma B16 lung metastases. Reduction of metastases also occurred in lungs transplanted with bacterial isolates from antibiotic-treated lungs. Aerosolized Lactobacillus rhamnosus strongly promoted immunity against B16 lung metastases as well. Furthermore, probiotics or antibiotics improved chemotherapy activity against advanced B16 metastases. Thus, we identify a role for lung microbiota in metastasis and show that its targeting via aerosolization is a therapy that can prevent metastases and enhance responses to chemotherapy. Le Noci et al. reveal that modulation of pulmonary microbiota by antibiotic or probiotic aerosolization decreases tumor growth in the lung. Antibiotic treatment induces a reduction of immunosuppressive cells in the lung, while probiotic administration promotes maturation of resident antigen-presenting cells.
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- 2018
8. Complex immune contextures characterise malignant peritoneal mesothelioma: Loss of adaptive immunological signature in the more aggressive histological types
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Tazzari, M, Brich, S, Tuccitto, A, Bozzi, F, Beretta, V, Spagnuolo, R, Negri, T, Stacchiotti, S, Deraco, M, Baratti, D, Camisaschi, C, Villa, A, Vergani, B, Rivoltini, L, Pilotti, S, Castelli, C, Spagnuolo, RD, Tazzari, M, Brich, S, Tuccitto, A, Bozzi, F, Beretta, V, Spagnuolo, R, Negri, T, Stacchiotti, S, Deraco, M, Baratti, D, Camisaschi, C, Villa, A, Vergani, B, Rivoltini, L, Pilotti, S, Castelli, C, and Spagnuolo, RD
- Abstract
Malignant peritoneal mesothelioma (MpM), arising in the setting of local inflammation, is a rare aggressive tumour with a poor prognosis and limited therapeutic options. The three major MpM histological variants, epithelioid (E-MpMs), biphasic, and sarcomatoid MpMs (S-MpMs), are characterised by an increased aggressiveness and enhanced levels of EZH2 expression. To investigate the MpM immune contexture along the spectrum of MpM histotypes, an extended in situ analysis was performed on a series of 14 cases. Tumour-infiltrating immune cells and their functionality were assessed by immunohistochemistry, immunofluorescence, qRT-PCR, and flow cytometry analysis. MpMs are featured by a complex immune landscape modulated along the spectrum of MpM variants. Tumour-infiltrating T cells and evidence for pre-existing antitumour immunity are mainly confined to E-MpMs. However, Th1-related immunological features are progressively impaired in the more aggressive forms of E-MpMs and completely lost in S-MpM. Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1. This study enriches the rising rationale for immunotherapy in MpM and points to the E-MpMs as the most immune-sensitive MpM histotypes, but it also suggests that synergistic interventions aimed at modifying the tumour microenvironment (TME) should be considered to make immunotherapy beneficial for these patients.
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- 2018
9. pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma
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Kuchuk, O, Tuccitto, A, Citterio, D, Huber, V, Camisaschi, C, Milione, M, Vergani, B, Villa, A, Alison, M, Carradori, S, Supuran, C, Rivoltini, L, Castelli, C, Mazzaferro, V, Kuchuk, Olga, Tuccitto, Alessandra, Citterio, Davide, Huber, Veronica, Camisaschi, Chiara, Milione, Massimo, Vergani, Barbara, Villa, Antonello, Alison, Malcolm Ronald, Carradori, Simone, Supuran, Claudiu T, Rivoltini, Licia, Castelli, Chiara, Mazzaferro, Vincenzo, Kuchuk, O, Tuccitto, A, Citterio, D, Huber, V, Camisaschi, C, Milione, M, Vergani, B, Villa, A, Alison, M, Carradori, S, Supuran, C, Rivoltini, L, Castelli, C, Mazzaferro, V, Kuchuk, Olga, Tuccitto, Alessandra, Citterio, Davide, Huber, Veronica, Camisaschi, Chiara, Milione, Massimo, Vergani, Barbara, Villa, Antonello, Alison, Malcolm Ronald, Carradori, Simone, Supuran, Claudiu T, Rivoltini, Licia, Castelli, Chiara, and Mazzaferro, Vincenzo
- Abstract
Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies
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- 2018
10. Adaptive Immunity in Fibrosarcomatous Dermatofibrosarcoma Protuberans and Response to Imatinib Treatment
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Tazzari, M., Indio, V., Vergani, B., Cecco, L. De, Rini, F., Negri, T., Camisaschi, C., Fiore, M., Stacchiotti, S., Dagrada, G.P., Casali, P.G., Gronchi, A., Astolfi, A., Pantaleo, M.A., Villa, A., Lombardo, C., Arienti, F., Pilotti, S., Rivoltini, L., Castelli, C., Tazzari, M., Indio, V., Vergani, B., Cecco, L. De, Rini, F., Negri, T., Camisaschi, C., Fiore, M., Stacchiotti, S., Dagrada, G.P., Casali, P.G., Gronchi, A., Astolfi, A., Pantaleo, M.A., Villa, A., Lombardo, C., Arienti, F., Pilotti, S., Rivoltini, L., and Castelli, C.
- Abstract
Item does not contain fulltext, Dermatofibrosarcoma protuberans (DFSP), although rare, is the most frequent skin sarcoma. Here, we focus on DFSP carrying the fibrosarcomatous transformation (FS-DFSP). FS-DFSP responds to imatinib (IM); however, tumor relapse often occurs. In a series of 21 pre- and post-treatment FS-DFSP samples, the present study explored the events that occur at the tumor site during IM therapy. Gene expression profile and immunohistochemistry analyses documented the occurrence of IM-induced senescence phenotype in the tumor cells and showed the accumulation of activated CD3+ T cells and CD163+CD14+ myeloid cells expressing the CD209 marker in post-therapy lesions. In post-IM specimens, the pathological response and tumor apoptosis were tightly associated with T-cell infiltration, thus suggesting the presence of an ongoing anti-tumor response, which was further confirmed by in vitro functional assays with CD3+ T cells isolated from an IM-responding FS-DFSP lesion. The integration of targeted therapies with immune therapies is currently under investigation to achieve longer tumor control. Our data outline the in situ immunological effects of IM and classify IM-treated FS-DFSP as potentially sensitive to immunotherapy, thus providing the rationale for further investigations of combination treatment for this soft-tissue sarcoma.
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- 2017
11. Adaptive Immunity in Fibrosarcomatous Dermatofibrosarcoma Protuberans and Response to Imatinib Treatment
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Tazzari, M, Indio, V, Vergani, B, De Cecco, L, Rini, F, Negri, T, Camisaschi, C, Fiore, M, Stacchiotti, S, Dagrada, G, Casali, P, Gronchi, A, Astolfi, A, Pantaleo, M, Villa, A, Lombardo, C, Arienti, F, Pilotti, S, Rivoltini, L, Castelli, C, Castelli, C., VERGANI, BARBARA, VILLA, ANTONELLO, Tazzari, M, Indio, V, Vergani, B, De Cecco, L, Rini, F, Negri, T, Camisaschi, C, Fiore, M, Stacchiotti, S, Dagrada, G, Casali, P, Gronchi, A, Astolfi, A, Pantaleo, M, Villa, A, Lombardo, C, Arienti, F, Pilotti, S, Rivoltini, L, Castelli, C, Castelli, C., VERGANI, BARBARA, and VILLA, ANTONELLO
- Abstract
Dermatofibrosarcoma protuberans (DFSP), although rare, is the most frequent skin sarcoma. Here, we focus on DFSP carrying the fibrosarcomatous transformation (FS-DFSP). FS-DFSP responds to imatinib (IM); however, tumor relapse often occurs. In a series of 21 pre- and post-treatment FS-DFSP samples, the present study explored the events that occur at the tumor site during IM therapy. Gene expression profile and immunohistochemistry analyses documented the occurrence of IM-induced senescence phenotype in the tumor cells and showed the accumulation of activated CD3+ T cells and CD163+CD14+ myeloid cells expressing the CD209 marker in post-therapy lesions. In post-IM specimens, the pathological response and tumor apoptosis were tightly associated with T-cell infiltration, thus suggesting the presence of an ongoing anti-tumor response, which was further confirmed by in vitro functional assays with CD3+ T cells isolated from an IM-responding FS-DFSP lesion. The integration of targeted therapies with immune therapies is currently under investigation to achieve longer tumor control. Our data outline the in situ immunological effects of IM and classify IM-treated FS-DFSP as potentially sensitive to immunotherapy, thus providing the rationale for further investigations of combination treatment for this soft-tissue sarcoma.
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- 2017
12. Tenth annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), SIENA, Italy, November 5-7, 2012
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Maio, M., Nicolay, H. J. M., Ascierto, P. A., Belardelli, F., Camerini, R., Colombo, M. P., Queirolo, P., Ridolfi, R., Russo, V., Parisi, G., Cutaia, O., Fonsatti, E., Parmiani, G., Mennonna, D., Carluccio, S., Bellone, M., Maccalli, C., Brendolan, A., Mondino, A., Corti, A., Bondanza, A., Locatelli, F., Seliger, B., Filaci, G., Rosato, A., Pittoni, P., Tazzari, M., Rivoltini, L., Anichini, A., Vallacchi, V., Zappasodi, R., Quaglino, E., Moresco, R. M., Camisaschi, C., Calabro, L., Ferrucci, P. F., Fratta, E., Ugel, S., van Baren, N., Guidoboni, M., Covre, A., Carbone, E., Aurisicchio, L., Palmieri, G., Di Giacomo, A. M., Volonte, A., Jachetti, E., and Sangiolo, D.
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Cancer Research ,medicine.medical_specialty ,business.industry ,Immunology ,Cancer ,medicine.disease ,NIBIT ,Oncology ,Family medicine ,Immunotherapy ,Networks ,Cancer, Immunology, Immunotherapy, Networks, NIBIT ,Immunology and Allergy ,Medicine ,business - Published
- 2013
13. Seventh annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), Siena, 1-3 October 2009
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Maio, M, Nicolay, Hj, Ascierto, Pa, Belardelli, F, Camerini, R, Colombo, Mp, Queirolo, P, Ridolfi, R, Russo, V, Fonsatti, E, Parmiani, G, Allavena P, N. I. B. I. T., Anichini, A, Bellone, M, Bronte, V, Calabrò, L, Camisaschi, C, Castelli, C, Danova, M, Di Giacomo AM, Di Nicola, M, Ferlazzo, G, Giovannoni, L, Hwu, P, Lehmann, F, Maccalli, C, Melero, I, Monsurro', Vladia, Montagna, D, Moschella, F, Ponzoni, M, Protti, Mp, Puccetti, P, Sangiolo, D, and Schuler, G.
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Cancer Research ,medicine.medical_specialty ,business.industry ,Immunology ,Neoplasms therapy ,Immunotherapy ,Immunomodulatory therapy ,adoptive cell therapy ,Oncology ,medicine ,Immunology and Allergy ,Medical physics ,business - Published
- 2010
14. Seventh annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), Siena, 1-3 October 2009
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Maio, M. (Michele), Nicolay, H.J.M. (Hugues J.M.), Ascierto, P.A. (Paolo Antonio), Belardelli, F. (Filipppo), Camerini, R. (Roberto), Colombo, M.P. (Mario P.), Queirolo, P. (Paola), Ridolfi, R. (Ruggero), Russo, V. (Vicenzo), Fonsati, E. (Ester), Parmiani, G. (Giorgio), Allavena, P. (P), Anichini, A. (A), Bellone, M. (M), Bronstein, J. (Judith), Calabro, L. (L), Camisaschi, C. (C), Castelli, C. (Chiara), Danova, M. (M), Di-Giacomo, A.M. (A.M.), Di-Nicola, M. (Massimo), Ferlazzo, G. (G.), Giovannoni, L. (L.), Hwu, P. (Patrick), Lehmann, F. (F.), Maccalli, C. (Cristina), Melero, I. (Ignacio), Monsurro, V. (V), Montagna, D. (D.), Moschella, F. (F.), Ponzoni, M. (M), Protti, M.P. (M.P.), Puccetti, P. (P), Sangiolo, D. (D.), and Shuler, G. (G)
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Neoplasms/therapy - Published
- 2010
15. Transcriptional profiling of melanoma sentinel nodes identify patients with poor outcome and reveal an association of CD30(+) T lymphocytes with progression
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Vallacchi, V, Vergani, E, Camisaschi, C, Deho, P, Cabras, A, Sensi, M, De Cecco, L, Bassani, N, Ambrogi, F, Carbone, A, Crippa, F, Vergani, B, Frati, P, Arienti, F, Patuzzo, R, Villa, A, Biganzoli, E, Canevari, S, Santinami, M, Castelli, C, Rivoltini, L, Rodolfo, M, VERGANI, BARBARA, VILLA, ANTONELLO, Rodolfo, M., Vallacchi, V, Vergani, E, Camisaschi, C, Deho, P, Cabras, A, Sensi, M, De Cecco, L, Bassani, N, Ambrogi, F, Carbone, A, Crippa, F, Vergani, B, Frati, P, Arienti, F, Patuzzo, R, Villa, A, Biganzoli, E, Canevari, S, Santinami, M, Castelli, C, Rivoltini, L, Rodolfo, M, VERGANI, BARBARA, VILLA, ANTONELLO, and Rodolfo, M.
- Abstract
Sentinel lymph nodes set the stance of the immune system to a localized tumor and are often the first site to be colonized by neoplastic cells that metastasize. To investigate how the presence of neoplastic cells in sentinel lymph nodes may trigger pathways associated with metastatic progression, we analyzed the transcriptional profiles of archival sentinel node biopsy specimens obtained from melanoma patients. Biopsies from positive nodes were selected for comparable tumor infiltration, presence or absence of further regional node metastases, and relapse at 5-year follow-up. Unsupervised analysis of gene expression profiles revealed immune response to be a major gene ontogeny represented. Among genes upregulated in patients with progressing disease, the TNF receptor family member CD30/TNFRSF8 was confirmed in biopsy specimens from an independent group of patients. Immunohistochemical analysis revealed higher numbers of CD30(+) lymphocytes in nodes from progressing patients compared with nonprogressing patients. Phenotypic profiling demonstrated that CD30(+) lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4(+)Foxp3(+) or PD1(+) subpopulations and CD4(-)CD8(-) T cells. CD30(+) T lymphocytes were increased in peripheral blood lymphocytes of melanoma patients at advanced disease stages. Our findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30(+) lymphocytes at those sites associate positively with melanoma progression.
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- 2014
16. Human plasmacytoid dendritic cells interact with gp96 via CD91 and regulate inflammatory responses
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De Filippo, A, Binder, R, Camisaschi, C, Beretta, V, Arienti, F, Villa, A, Della Mina, P, Parmiani, G, Rivoltini, L, Castelli, C, Binder, RJ, Castelli, C., VILLA, ANTONELLO, De Filippo, A, Binder, R, Camisaschi, C, Beretta, V, Arienti, F, Villa, A, Della Mina, P, Parmiani, G, Rivoltini, L, Castelli, C, Binder, RJ, Castelli, C., and VILLA, ANTONELLO
- Abstract
Glucose-regulated stress protein gp96 is known to be involved in the host response to pathogens and to cancer. Our study explored the relationships between gp96 and human blood plasmacytoid dendritic cells (pDC) and proved that gp96 directly targets pDC by a receptor-dependent interaction. Competition studies identified CD91 as a gp96 receptor on pDC, and laser confocal imaging indicated that CD91 triggering was followed by gp96 endocytosis and trafficking into early endosomes and later into the endoplasmic reticulum compartment. Using two alternative Abs, we showed that human blood pDC reproducibly expressed CD91, although different levels of expression were detectable among the analyzed donors. Moreover, CpG-matured pDC displayed CD91 receptor up-regulation that correlated with an increased gp96 binding. Functionally, gp96-pDC interaction activated the NF-kappaB pathway, leading to the nuclear translocation of the NF-kappaB complex. gp96-treated pDC maintained an immature phenotype, while they down-modulated the release of IL-8, suggesting an anti-inflammatory role of this pathway, and they strongly up-regulated the cell surface expression of the gp96 receptor CD91. CpG-matured or gp96-treated pDC, expressing high levels of the gp96 receptor CD91, antagonized the gp96-induced activation of monocyte-derived dendritic cells in terms of cell surface phenotype and cytokine production. Altogether, these results suggest that gp96-pDC interaction might represent an active mechanism controlling the strength of the immune response to free, extracellular available gp96; this mechanism could be particularly relevant in wounds and chronic inflammation.
- Published
- 2008
17. Final results of a dose-finding phase II trial with a triple combination therapy in metastatic renal cell cancer (mRCC): Bevacizumab (B) plus immunotherapy (IT) plus chemotherapy (C) (BIC), antitumor effects, and variations of circulating T-regulatory cells (TREG).
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Passalacqua, R., primary, Buti, S., additional, Brighenti, M., additional, Rivoltini, L., additional, Castelli, C., additional, Camisaschi, C., additional, Simonelli, C., additional, Lo Re, G., additional, Mattioli, R., additional, and Lazzarelli, S., additional
- Published
- 2010
- Full Text
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18. Bevacizumab (B) plus low-doses immunotherapy (IT) plus chemotherapy (CT) (BIC) in metastatic renal cell cancer (mRCC): Antitumor effects and variations of T-regulatory cells (Treg) and other T lymphocytes subsets. A study of the Italian Oncology Group for Clinical Research (GOIRC)
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Passalacqua, R., primary, Buti, S., additional, Rivoltini, L., additional, Castelli, C., additional, Camisaschi, C., additional, Simonelli, C., additional, Lo Re, G., additional, Mattioli, R., additional, Mazza, G., additional, Brighenti, M., additional, and Lazzarelli, S., additional
- Published
- 2008
- Full Text
- View/download PDF
19. BEVACIZUMAB (B) PLUS IMMUNOTHERAPY (IT) PLUS CHEMOTHERAPY (C) (BIC) IN METASTATIC RENAL CELL CANCER (MRCC): RESULTS AND EVALUATION OF CIRCULATING T-REGULATORY CELLS (TREG) AND OTHER CYTOKINES. A GOIRC STUDY
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Passalacqua, R., Buti, S., Simonelli, C., Rivoltini, L., Castelli, C., Camisaschi, C., Lo Re, G., Arben Lleshi, Donnini, M., and Lazzarelli, S.
20. Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer
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Camisaschi C, Vallacchi V, Vergani E, Marcella Tazzari, Ferro S, Tuccitto A, Kuchuk O, Shahaj E, Sulsenti R, Castelli C, Rodolfo M, Rivoltini L, and Huber V
21. FINAL RESULTS OF A DOSE-FINDING PHASE II TRIAL WITH A TRIPLE COMBINATION THERAPY IN METASTATIC RENAL CELL CANCER (MRCC): BEVACIZUMAB (B) PLUS IMMUNOTHERAPY (IT) PLUS CHEMOTHERAPY (C) (BIC). ANTITUMOR EFFECTS AND VARIATIONS OF CIRCULATING T-REGULATORY CELLS (TREG) AND OTHER T LYMPHOCYTES SUBSETS
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Passalacqua, R., Buti, S., Brighenti, M., Licia Rivoltini, Castelli, C., Camisaschi, C., Simonelli, C., Lo Re, G., Mattioli, R., Mazza, G., Dalla Chiesa, M., Tomasello, G., Negri, F., and Lazzarelli, S.
22. A subset of human LAG-3+Tregs shows characteristics of follicular Tregs
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Camisaschi, C., Cecco, L., Vergani, B., Beretta, V., Rini, F., Cabras, A., Giovanna Cutrona, Di Nicola, M., Milione, M., Arienti, F., Villa, A., Rivoltini, L., and Castelli, C.
23. A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer
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Ugo Pastorino, Nadia Zaffaroni, Orazio Fortunato, Chiara Camisaschi, Giuliana Pollaci, Francesca Giovinazzo, Valeria Cancila, Giulia Bertolini, Massimo Milione, Massimo Moro, Federica Facchinetti, Monica Tortoreto, Giovanni Centonze, Claudia Chiodoni, Stefania Scala, Gabriella Sozzi, Crescenzo D'Alterio, Alessandro De Toma, Giulia Taiè, Luca Roz, Claudio Tripodo, Giuseppe Lo Russo, Bertolini G., Cancila V., Milione M., Lo Russo G., Fortunato O., Zaffaroni N., Tortoreto M., Centonze G., Chiodoni C., Facchinetti F., Pollaci G., Taie G., Giovinazzo F., Moro M., Camisaschi C., De Toma A., D'Alterio C., Pastorino U., Tripodo C., Scala S., Sozzi G., and Roz L.
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Male ,Receptors, CXCR4 ,Stromal cell ,Lung Neoplasms ,Settore MED/08 - Anatomia Patologica ,Monocytes ,Metastasis ,Mice ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Drug Discovery ,Genetics ,Medicine ,Settore MED/05 - Patologia Clinica ,Animals ,Humans ,Drug Interactions ,AC133 Antigen ,Neoplasm Metastasis ,Lung cancer ,Molecular Biology ,Pharmacology ,Cisplatin ,CXCR4 antagonist ,chemotherapy, combination therapy, inflammatory monocytes, lung cancer stem cells, metastasis, peptide anti-CXCR4, SDF-1/CXCR4 axis ,business.industry ,medicine.disease ,Primary tumor ,Xenograft Model Antitumor Assays ,Extravasation ,Chemokine CXCL12 ,medicine.anatomical_structure ,RAW 264.7 Cells ,A549 Cells ,Cancer research ,Neoplastic Stem Cells ,Molecular Medicine ,Bone marrow ,business ,Peptides ,medicine.drug - Abstract
Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+CXCR4+ metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease.
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- 2020
24. Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk
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Federica Facchinetti, Massimo Milione, Chiara Camisaschi, Francesca Andriani, Agata Cova, Gabriella Sozzi, Orazio Fortunato, Laura Caleca, Davide Conte, Veronica Huber, Ugo Pastorino, Massimo Moro, Valeria Cancila, Giovanni Centonze, Carla Verri, Luca Roz, Cristina Borzi, Claudio Tripodo, Chiara Castelli, Mattia Boeri, Fortunato O., Borzi C., Milione M., Centonze G., Conte D., Boeri M., Verri C., Moro M., Facchinetti F., Andriani F., Roz L., Caleca L., Huber V., Cova A., Camisaschi C., Castelli C., Cancila V., Tripodo C., Pastorino U., and Sozzi G.
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Male ,Cancer Research ,Cell type ,Lung Neoplasms ,Carcinogenesis ,Neutrophils ,Macrophage ,Mice, SCID ,Biology ,medicine.disease_cause ,Molecular Cancer Biology ,03 medical and health sciences ,Paracrine signalling ,Mice ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,microRNA ,medicine ,Tobacco Smoking ,Animals ,Humans ,Circulating MicroRNA ,Lung cancer ,Lung ,Carcinogenesi ,Tumor microenvironment ,Animal ,Macrophages ,Gene Expression Profiling ,Neutrophil ,STAT4 Transcription Factor ,medicine.disease ,microenvironment ,Xenograft Model Antitumor Assays ,3. Good health ,Gene Expression Regulation, Neoplastic ,Lung Neoplasm ,MicroRNAs ,lung cancer ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,Tumor Escape ,Human - Abstract
miRNAs play a central role in the complex signaling network of cancer cells with the tumor microenvironment. Little is known on the origin of circulating miRNAs and their relationship with the tumor microenvironment in lung cancer. Here, we focused on the cellular source and relative contribution of different cell types to circulating miRNAs composing our risk classifier of lung cancer using in vitro/in vivo models and clinical samples. A cell‐type specific expression pattern and topography of several miRNAs such as mir‐145 in fibroblasts, mir‐126 in endothelial cells, mir‐133a in skeletal muscle cells was observed in normal and lung cancer tissues. Granulocytes and platelets are the major contributors of miRNAs release in blood. miRNAs modulation observed in plasma of lung cancer subjects was consistent with de‐regulation of the same miRNAs observed during immunosuppressive conversion of immune cells. In particular, activated neutrophils showed a miRNA profile mirroring that observed in plasma of lung cancer subjects. Interestingly mir‐320a secreted by neutrophils of high‐risk heavy‐smokers promoted an M2‐like protumorigenic phenotype through downregulation of STAT4 when shuttled into macrophages. These findings suggest a multifactorial and nonepithelial cell‐autonomous origin of circulating miRNAs associated with risk of lung cancer and that circulating miRNAs may act in paracrine signaling with causative role in lung carcinogenesis and immunosuppression., What's new? microRNAs play a central role in the complex signaling network of cancer cells with the tumor microenvironment. However, little is known on the origin of circulating miRNAs and their mechanisms of action. This study found a multifactorial and non‐epithelial cell‐autonomous origin of circulating miRNAs associated with lung cancer risk. The findings also suggest a link between an immunosuppressive and pro‐tumorigenic microenvironment and modulation of circulating miRNAs associated with lung cancer risk. The authors propose a novel mechanism whereby miRNA released by neutrophils induce macrophage polarization to support lung cancer growth, highlighting the potential for reprogramming macrophages toward an anti‐tumor polarization.
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- 2019
25. Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types
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Silvia Brich, Chiara Camisaschi, Antonello Villa, Tiziana Negri, Valeria Beretta, Silvana Pilotti, Chiara Castelli, Rosalin Dolores Spagnuolo, Silvia Stacchiotti, Alessandra Tuccitto, Licia Rivoltini, Barbara Vergani, Fabio Bozzi, Dario Baratti, Marcella Tazzari, Marcello Deraco, Tazzari, M, Brich, S, Tuccitto, A, Bozzi, F, Beretta, V, Spagnuolo, R, Negri, T, Stacchiotti, S, Deraco, M, Baratti, D, Camisaschi, C, Villa, A, Vergani, B, Rivoltini, L, Pilotti, S, and Castelli, C
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0301 basic medicine ,Mesothelioma ,Lung Neoplasms ,Carcinogenesis ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Adaptive Immunity ,T-Lymphocytes, Regulatory ,B7-H1 Antigen ,Peritoneal Neoplasm ,0302 clinical medicine ,Tumor Microenvironment ,Immunology and Allergy ,Medicine ,Carcinogenesi ,Peritoneal Neoplasms ,B-Lymphocytes, Regulatory ,Paraffin Embedding ,General Medicine ,Acquired immune system ,Immunohistochemistry ,Th1 Cell ,Phenotype ,030220 oncology & carcinogenesis ,Human ,Research Article ,lcsh:Immunologic diseases. Allergy ,Article Subject ,Immunology ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Immunosuppression Therapy ,Tumor microenvironment ,business.industry ,Mesothelioma, Malignant ,Immunotherapy ,Th1 Cells ,medicine.disease ,Immune checkpoint ,Lung Neoplasm ,030104 developmental biology ,Tumor Escape ,Cancer research ,lcsh:RC581-607 ,business ,Immunosuppression - Abstract
Malignant peritoneal mesothelioma (MpM), arising in the setting of local inflammation, is a rare aggressive tumour with a poor prognosis and limited therapeutic options. The three major MpM histological variants, epithelioid (E-MpMs), biphasic, and sarcomatoid MpMs (S-MpMs), are characterised by an increased aggressiveness and enhanced levels of EZH2 expression. To investigate the MpM immune contexture along the spectrum of MpM histotypes, an extended in situ analysis was performed on a series of 14 cases. Tumour-infiltrating immune cells and their functionality were assessed by immunohistochemistry, immunofluorescence, qRT-PCR, and flow cytometry analysis. MpMs are featured by a complex immune landscape modulated along the spectrum of MpM variants. Tumour-infiltrating T cells and evidence for pre-existing antitumour immunity are mainly confined to E-MpMs. However, Th1-related immunological features are progressively impaired in the more aggressive forms of E-MpMs and completely lost in S-MpM. Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1. This study enriches the rising rationale for immunotherapy in MpM and points to the E-MpMs as the most immune-sensitive MpM histotypes, but it also suggests that synergistic interventions aimed at modifying the tumour microenvironment (TME) should be considered to make immunotherapy beneficial for these patients.
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- 2018
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26. pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma
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Chiara Castelli, Simone Carradori, Licia Rivoltini, Davide Citterio, Barbara Vergani, Antonello Villa, Massimo Milione, Vincenzo Mazzaferro, Olga Kuchuk, Malcolm R. Alison, Alessandra Tuccitto, Claudiu T. Supuran, Chiara Camisaschi, Veronica Huber, Kuchuk, O, Tuccitto, A, Citterio, D, Huber, V, Camisaschi, C, Milione, M, Vergani, B, Villa, A, Alison, M, Carradori, S, Supuran, C, Rivoltini, L, Castelli, C, and Mazzaferro, V
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,medicine.medical_treatment ,Immunology ,immunosuppressive cells ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,ph regulatory molecules ,medicine ,tumor microenvironment ,Immunology and Allergy ,Glycolysis ,immunosuppressive cell ,Original Research ,Tumor microenvironment ,therapy ,Chemistry ,Mesenchymal stem cell ,Immunosuppression ,Metabolism ,hepatocellular carcinoma ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Immune checkpoint ,pH regulatory molecule ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,lcsh:RC581-607 ,Ex vivo - Abstract
Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.
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- 2018
27. Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression
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Antonello Domenico Cabras, Paola Deho, Chiara Camisaschi, Monica Rodolfo, Barbara Vergani, Federica Crippa, Niccolò Bassani, Antonino Carbone, Roberto Patuzzo, Silvana Canevari, Paola Frati, Flavio Arienti, Mario Santinami, Loris De Cecco, Licia Rivoltini, Viviana Vallacchi, Elia Biganzoli, Federico Ambrogi, Chiara Castelli, Antonello Villa, Marialuisa Sensi, Elisabetta Vergani, Vallacchi, V, Vergani, E, Camisaschi, C, Deho, P, Cabras, A, Sensi, M, De Cecco, L, Bassani, N, Ambrogi, F, Carbone, A, Crippa, F, Vergani, B, Frati, P, Arienti, F, Patuzzo, R, Villa, A, Biganzoli, E, Canevari, S, Santinami, M, Castelli, C, Rivoltini, L, and Rodolfo, M
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Cancer Research ,Pathology ,medicine.medical_specialty ,CD30 ,T-Lymphocytes ,Population ,Ki-1 Antigen ,Antigens, CD30 ,Immune system ,Biopsy ,medicine ,Humans ,education ,Melanoma ,education.field_of_study ,medicine.diagnostic_test ,Sentinel Lymph Node Biopsy ,business.industry ,Computational Biology ,FOXP3 ,Sentinel node ,medicine.disease ,Immunohistochemistry ,Treatment Outcome ,T-Lymphocyte ,Oncology ,Disease Progression ,Transcriptome ,business ,CD8 ,Human - Abstract
Sentinel lymph nodes set the stance of the immune system to a localized tumor and are often the first site to be colonized by neoplastic cells that metastasize. To investigate how the presence of neoplastic cells in sentinel lymph nodes may trigger pathways associated with metastatic progression, we analyzed the transcriptional profiles of archival sentinel node biopsy specimens obtained from melanoma patients. Biopsies from positive nodes were selected for comparable tumor infiltration, presence or absence of further regional node metastases, and relapse at 5-year follow-up. Unsupervised analysis of gene expression profiles revealed immune response to be a major gene ontogeny represented. Among genes upregulated in patients with progressing disease, the TNF receptor family member CD30/TNFRSF8 was confirmed in biopsy specimens from an independent group of patients. Immunohistochemical analysis revealed higher numbers of CD30+ lymphocytes in nodes from progressing patients compared with nonprogressing patients. Phenotypic profiling demonstrated that CD30+ lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4+Foxp3+ or PD1+ subpopulations and CD4−CD8− T cells. CD30+ T lymphocytes were increased in peripheral blood lymphocytes of melanoma patients at advanced disease stages. Our findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30+ lymphocytes at those sites associate positively with melanoma progression. Cancer Res; 74(1); 130–40. ©2014 AACR.
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- 2014
28. Limited Induction of Tumor Cross-Reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen Class I–Modified Peptides
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Chiara Castelli, Marco Asioli, Paola Filipazzi, Claudia Lombardo, Michele Maio, Antonello Villa, Chiara Camisaschi, Riccardo Danielli, Gabrina Tragni, Gloria Sovena, Paola Frati, Gianluigi Rigamonti, Roberto Patuzzo, Licia Rivoltini, Paola Squarcina, Andrea Maurichi, Giorgio Parmiani, Agata Cova, Luigi Mariani, Felicetta Giardino, Annabella Di Florio, Lorenzo Pilla, Mario Santinami, Vanna Chiarion-Sileni, Filipazzi, P, Pilla, L, Mariani, L, Patuzzo, R, Castelli, C, Camisaschi, C, Maurichi, A, Cova, A, Rigamonti, G, Giardino, F, Di Florio, A, Asioli, M, Frati, P, Sovena, G, Squarcina, P, Maio, M, Danielli, R, Chiarion Sileni, V, Villa, A, Lombardo, C, Tragni, G, Santinami, M, Parmiani, G, and Rivoltini, L
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Cancer Research ,T-Lymphocytes ,medicine.medical_treatment ,Epitopes, T-Lymphocyte ,Human leukocyte antigen ,Cross Reactions ,Cancer Vaccines ,MART-1 Antigen ,Immune system ,medicine ,Humans ,Melanoma ,Neoplasm Staging ,business.industry ,Histocompatibility Antigens Class I ,Cancer ,tumor recognition ,medicine.disease ,Vaccination ,Treatment Outcome ,Oncology ,Immunization ,Case-Control Studies ,Vaccines, Subunit ,Immunology ,Peptides ,business ,Immunologic Memory ,Adjuvant ,CD8 - Abstract
Purpose: The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III). Experimental Design: Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201–restricted modified peptides (Melan-A/MART-1[27L], gp100[210M], NY-ESO-1[165V], and Survivin[97M]) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m2) and low-dose IL-2 (3 × 106 IU). The immune responses were monitored using ex vivo IFN-γ–ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays. Results: Vaccination induced a rapid and persistent increase in specific effector memory CD8+ T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells. Conclusions: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8+ T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease. Clin Cancer Res; 18(23); 6485–96. ©2012 AACR.
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- 2012
29. Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3
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Chiara Camisaschi, Licia Rivoltini, Antonello Villa, Frédéric Triebel, Mario Santinami, Monica Rodolfo, Flavio Arienti, Chiara Castelli, Antonello Domenico Cabras, Elisabetta Vergani, Barbara Vergani, Annamaria De Filippo, Valeria Beretta, Camisaschi, C, De Filippo, A, Beretta, V, Vergani, B, Villa, A, Vergani, E, Santinami, M, Cabras, A, Arienti, F, Triebel, F, Rodolfo, M, Rivoltini, L, and Castelli, C
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Skin Neoplasms ,Cell ,Cercopithecus aethiop ,Dermatology ,Dendritic Cell ,Biochemistry ,Monocytes ,Immune system ,In vivo ,Cell Movement ,Antigens, CD ,COS Cell ,Cell Line, Tumor ,Chlorocebus aethiops ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Skin Neoplasm ,Interleukin 6 ,Molecular Biology ,Melanoma ,Chemokine CCL2 ,Tumor microenvironment ,biology ,Animal ,Interleukin-6 ,hemic and immune systems ,Dendritic Cells ,Cell Biology ,Acquired immune system ,medicine.disease ,Lymphocyte Activation Gene 3 Protein ,medicine.anatomical_structure ,COS Cells ,Immunology ,Cancer research ,biology.protein ,Ex vivo ,Human - Abstract
Plasmacytoid dendritic cells (pDCs) at tumor sites are often tolerogenic. Although pDCs initiate innate and adaptive immunity upon Toll-like receptor (TLR) triggering by pathogens, TLR-independent signals may be responsible for pDC activation and immune suppression in the tumor inflammatory environment. To identify molecules that are potentially involved in alternative pDC activation, we explored the expression and function of lymphocyte activation gene 3 (LAG-3) in human pDCs. In this report, we showed the expression of LAG-3 on the cell surface of a subset of circulating human pDCs. LAG-3+ pDCs exhibited a partially mature phenotype and were enriched at tumor sites in samples from melanoma patients. We found that LAG-3 interacted with major histocompatibility complex class II (MHC-II) to induce TLR-independent activation of pDCs with limited IFNα and enhanced IL-6 production. This in vitro cytokine profile of LAG-3-activated pDCs paralleled that of tumor-associated pDCs analyzed ex vivo. By confocal microscopy, LAG-3+ pDCs detected in melanoma-invaded lymph nodes (LNs) stained positive for IL-6 and preferentially localized near melanoma cells. These results suggest that LAG-3-mediated activation of pDCs takes place in vivo at tumor sites, and it is in part responsible for directing an immune-suppressive environment.
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- 2014
30. Effects of cyclophosphamide and IL-2 on regulatory CD4(+) T cell frequency and function in melanoma patients vaccinated with HLA-class I peptides: impact on the antigen-specific T cell response
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Antonello Villa, Ludmila Umansky, Chiara Camisaschi, Michele Maio, Philipp Beckhove, Giorgio Parmiani, Gabrina Tragni, Barbara Vergani, Vanna Chiarion-Sileni, Marcella Tazzari, Agata Cova, Chiara Castelli, Valeria Beretta, Emilio Berti, Paola Filipazzi, Lorenzo Pilla, Viktor Umansky, Licia Rivoltini, Roberto Patuzzo, Andrea Maurichi, Chiara Casati, Mario Santinami, Camisaschi, C, Filipazzi, P, Tazzari, M, Casati, C, Beretta, V, Pilla, L, Patuzzo, R, Maurichi, A, Cova, A, Maio, M, Chiarion Sileni, V, Tragni, G, Santinami, M, Vergani, B, Villa, A, Berti, E, Umansky, L, Beckhove, P, Umansky, V, Parmiani, G, Rivoltini, L, and Castelli, C
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CD4-Positive T-Lymphocytes ,Male ,Cancer Research ,Skin Neoplasms ,Time Factors ,T-Lymphocytes ,medicine.medical_treatment ,CD8-Positive T-Lymphocytes ,Immunosuppressive Agent ,Immunology and Allergy ,Lymph node ,Melanoma ,ELISPOT ,hemic and immune systems ,Regulatory T cells ,Middle Aged ,Flow Cytometry ,Vaccination ,Phenotype ,medicine.anatomical_structure ,Oncology ,CD4-Positive T-Lymphocyte ,Original Article ,Female ,Immunotherapy ,Immunosuppressive Agents ,Human ,medicine.drug ,Adult ,Interleukin 2 ,Time Factor ,T cell ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Cyclophosphamide, Immunotherapy, Melanoma, Regulatory T cells ,Interferon-gamma ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Humans ,Skin Neoplasm ,Antineoplastic Agents, Alkylating ,Cyclophosphamide ,Aged ,business.industry ,Histocompatibility Antigens Class I ,CD8-Positive T-Lymphocyte ,T-Lymphocyte ,Leukocytes, Mononuclear ,Interleukin-2 ,business ,Regulatory T cell ,CD8 - Abstract
The frequency and function of regulatory T cells (Tregs) were studied in stage II–III melanoma patients who were enrolled in a phase II randomized trial of vaccination with HLA-A*0201-modified tumor peptides versus observation. The vaccinated patients received low-dose cyclophosphamide (CTX) and low-dose interleukin-2 (IL-2). Tregs were analyzed in the lymph nodes (LNs) of stage III patients who were undergoing complete lymph node dissection and in peripheral blood mononuclear cells (PBMCs) collected before vaccination and at different time points during the vaccination period. The LNs of the vaccinated patients, which were surgically removed after two rounds of vaccination and one dose of CTX, displayed a low frequency of Tregs and a less immunosuppressive environment compared with those of the untreated patients. The accurate time-course analysis of the PBMCs of patients enrolled in the vaccination arm indicated a limited and transient modulation in the frequencies of Tregs in PBMCs collected after low-dose CTX administration and a strong Treg boost in those PBMCs collected after low-dose IL-2 administration. However, a fraction of the IL-2-boosted Tregs was functionally modulated to a Th-1-like phenotype in the vaccinated patients. Moreover, low-dose IL-2 promoted the concomitant expansion of conventional activated CD4+ T cells. Despite the amplification of Tregs, IL-2 administration maintained or further increased the number of antigen-specific CD8+ T cells that were induced by vaccination as demonstrated by the ex vivo human leukocyte antigen-multimer staining and IFN-γ ELISpot assays. Our study suggests that the use of CTX as a Treg modulator should be revised in terms of the administration schedule and of patients who may benefit from this drug treatment. Despite the Treg expansion that was observed in this study, low-dose IL-2 is not detrimental to the functional activities of vaccine-primed CD8+ T cell effectors when used in the inflammatory environment of vaccination. Electronic supplementary material The online version of this article (doi:10.1007/s00262-013-1397-7) contains supplementary material, which is available to authorized users.
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- 2013
31. Human plasmacytoid dendritic cells interact with gp96 via CD91 and regulate inflammatory responses
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Chiara Camisaschi, Pamela Della Mina, Antonello Villa, Giorgio Parmiani, Chiara Castelli, Flavio Arienti, Robert J. Binder, Licia Rivoltini, Annamaria De Filippo, Valeria Beretta, De Filippo, A, Binder, R, Camisaschi, C, Beretta, V, Arienti, F, Villa, A, Della Mina, P, Parmiani, G, Rivoltini, L, and Castelli, C
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Cell signaling ,Endosome ,Cellular differentiation ,medicine.medical_treatment ,Immunology ,Inflammation ,macromolecular substances ,Cell Communication ,Biology ,Endocytosis ,Dendritic Cell ,Monocyte ,Monocytes ,Antigens, CD ,medicine ,Immunology and Allergy ,Humans ,Receptor ,Coculture Technique ,Inflammation Mediator ,Cells, Cultured ,Membrane Glycoproteins ,Endoplasmic reticulum ,hemic and immune systems ,Cell Differentiation ,Dendritic Cells ,Coculture Techniques ,Cell biology ,Cytokine ,Membrane Glycoprotein ,medicine.symptom ,Inflammation Mediators ,Low Density Lipoprotein Receptor-Related Protein-1 ,Protein Binding ,Human - Abstract
Glucose-regulated stress protein gp96 is known to be involved in the host response to pathogens and to cancer. Our study explored the relationships between gp96 and human blood plasmacytoid dendritic cells (pDC) and proved that gp96 directly targets pDC by a receptor-dependent interaction. Competition studies identified CD91 as a gp96 receptor on pDC, and laser confocal imaging indicated that CD91 triggering was followed by gp96 endocytosis and trafficking into early endosomes and later into the endoplasmic reticulum compartment. Using two alternative Abs, we showed that human blood pDC reproducibly expressed CD91, although different levels of expression were detectable among the analyzed donors. Moreover, CpG-matured pDC displayed CD91 receptor up-regulation that correlated with an increased gp96 binding. Functionally, gp96-pDC interaction activated the NF-κB pathway, leading to the nuclear translocation of the NF-κB complex. gp96-treated pDC maintained an immature phenotype, while they down-modulated the release of IL-8, suggesting an anti-inflammatory role of this pathway, and they strongly up-regulated the cell surface expression of the gp96 receptor CD91. CpG-matured or gp96-treated pDC, expressing high levels of the gp96 receptor CD91, antagonized the gp96-induced activation of monocyte-derived dendritic cells in terms of cell surface phenotype and cytokine production. Altogether, these results suggest that gp96-pDC interaction might represent an active mechanism controlling the strength of the immune response to free, extracellular available gp96; this mechanism could be particularly relevant in wounds and chronic inflammation.
32. Parkin activates innate immunity and promotes anti-tumor immune responses.
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Perego M, Yeon M, Agarwal E, Milcarek AT, Bertolini I, Camisaschi C, Ghosh JC, Tang HY, Grandvaux N, Ruscetti M, Kossenkov AV, Preston-Alp S, Tempera I, Auslander N, and Altieri DC
- Abstract
The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and a link to tumor suppression undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease was epigenetically silenced in cancer and its re-expression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NFκB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8 T cell markers, lowered the expression of immune inhibitory receptors, TIM3 and LAG3, and stimulated high content of the self-renewal/stem cell factor, TCF1. Parkin-induced CD8 T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth, in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.
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- 2024
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33. NaCl enhances CD8 + T cell effector functions in cancer immunotherapy.
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Scirgolea C, Sottile R, De Luca M, Susana A, Carnevale S, Puccio S, Ferrari V, Lise V, Contarini G, Scarpa A, Scamardella E, Feno S, Camisaschi C, De Simone G, Basso G, Giuliano D, Mazza EMC, Gattinoni L, Roychoudhuri R, Voulaz E, Di Mitri D, Simonelli M, Losurdo A, Pozzi D, Tsui C, Kallies A, Timo S, Martano G, Barberis E, Manfredi M, Rescigno M, Jaillon S, and Lugli E
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- Animals, Mice, Humans, Cell Differentiation, Tumor Microenvironment immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms drug therapy, Cell Line, Tumor, Interferon-gamma metabolism, Glutamine metabolism, Mice, Inbred C57BL, Immunotherapy, Adoptive methods, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Sodium Chloride, Immunotherapy methods
- Abstract
CD8
+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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34. Immunological characterization of a long-lasting response in a patient with metastatic triple-negative breast cancer treated with PD-1 and LAG-3 blockade.
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Rivoltini L, Camisaschi C, Fucà G, Paolini B, Vergani B, Beretta V, Damian S, Duca M, Cresta S, Magni M, Leone BE, Castelli C, de Braud F, De Santis F, and Di Nicola M
- Subjects
- Humans, Programmed Cell Death 1 Receptor metabolism, CD8-Positive T-Lymphocytes, Treatment Outcome, B7-H1 Antigen, Triple Negative Breast Neoplasms pathology, Antineoplastic Agents therapeutic use
- Abstract
In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3
+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade.Trial registration: NCT02460224. Registered 02/06/2015., (© 2024. The Author(s).)- Published
- 2024
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35. Reduction of Staphylococcus epidermidis in the mammary tumor microbiota induces antitumor immunity and decreases breast cancer aggressiveness.
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Bernardo G, Le Noci V, Ottaviano E, De Cecco L, Camisaschi C, Guglielmetti S, Di Modica M, Gargari G, Bianchi F, Indino S, Sartori P, Borghi E, Sommariva M, Tagliabue E, Triulzi T, and Sfondrini L
- Subjects
- Mice, Animals, RNA, Ribosomal, 16S genetics, Ampicillin pharmacology, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Tumor Microenvironment, Staphylococcus epidermidis, Mammary Neoplasms, Animal
- Abstract
The mammary gland hosts a microbiota, which differs between malignant versus normal tissue. We found that aerosolized antibiotics decrease murine mammary tumor growth and strongly limit lung metastasis. Oral absorbable antibiotics also reduced mammary tumors. In ampicillin-treated nodules, the immune microenvironment consisted of an M1 profile and improved T cell/macrophage infiltration. In these tumors, we noted an under-representation of microbial recognition and complement pathways, supported by TLR2/TLR7 protein and C3-fragment deposition reduction. By 16S rRNA gene profiling, we observed increased Staphylococcus levels in untreated tumors, among which we isolated Staphylococcus epidermidis, which had potent inflammatory activity and increased Tregs. Conversely, oral ampicillin lowered Staphylococcus epidermidis in mammary tumors and expanded bacteria promoting an M1 phenotype and reducing MDSCs and tumor growth. Ampicillin/paclitaxel combination improved the chemotherapeutic efficacy. Notably, an Amp-like signature, based on genes differentially expressed in murine tumors, identified breast cancer patients with better prognosis and high immune infiltration that correlated with a bacteria response signature. This study highlights the significant influence of mammary tumor microbiota on local immune status and the relevance of its treatment with antibiotics, in combination with breast cancer therapies., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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36. Y 90 -radioembolisation in hepatocellular carcinoma induces immune responses calling for early treatment with multiple checkpoint blockers.
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Rivoltini L, Bhoori S, Camisaschi C, Bergamaschi L, Lalli L, Frati P, Citterio D, Castelli C, and Mazzaferro V
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- Humans, Immunotherapy, Carcinoma, Hepatocellular radiotherapy, Liver Neoplasms radiotherapy, Embolization, Therapeutic
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2023
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37. Dampening of cytotoxic innate lymphoid cells: A new tumour immune escape mechanism in B cell non-Hodgkin's lymphoma.
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Roma S, Camisaschi C, Mancuso P, Trabanelli S, Vanazzi A, Villa S, Prati D, Fiori S, Lorenzini D, Tabanelli V, Pileri S, Tarella C, Jandus C, and Bertolini F
- Subjects
- Humans, Tumor Escape, Immunity, Innate, Lymphocytes, Killer Cells, Natural, Antineoplastic Agents, Neoplasms pathology, Lymphoma, Non-Hodgkin pathology
- Abstract
The role and regulation of innate immune cells is poorly understood in B-cell non-Hodgkin lymphoma (NHL). As natural killer (NK) cells, helper innate lymphoid cells (ILCs) are lymphocytes endowed with either anti- or pro-tumour activity and involved in inflammatory processes. In our ex vivo analysis of NK cells and ILCs from NHL patients, we observed that, in comparison to healthy donors (HD), the frequency of the cytotoxic subset of NK cells, the CD16
+ NK, decreased in patients' peripheral blood. In general, circulating NK cells showed a pro-tumorigenic phenotype, while ILCs displayed a more activated/cytotoxic phenotype. Conversely, at the tumour site, in patients' lymph nodes, ILCs showed a low expression of granzyme.In vitromixed lymphocyte-tumour cell cultures with HD PBMCs and NHL cell lines demonstrated that ILC cytotoxic potential was lowered by the presence of tumour cells but, in the absence of T regulatory cells (Tregs), their cytolytic potential was recovered. Our data shed novel light on dysfunctional innate immunity in NHL. We suggest a new mechanism of tumour immuno-escape based on the reduction of cell cytotoxicity involving ILCs and likely controlled by Tregs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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38. Validity of Anti-PSMA ScFvD2B as a Theranostic Tool: A Narrative-Focused Review.
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Frigerio B, Luison E, Desideri A, Iacovelli F, Camisaschi C, Seregni EC, Canevari S, and Figini M
- Abstract
Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in other normal tissues and highly overexpressed in PCa, represents a reliable marker ideal for imaging and therapy. The development of anti-PSMA antibodies, such as D2B, demonstrated slow clearance of intact antibodies compared with fragments resulting in low tumor-to-blood ratios; however, the modular structural and functional nature of antibodies allowed the generation of smaller fragments, such as scFvs. In this review of the anti-PSMA antibody fragment scFvD2B, we combined further characterization of its biomolecular and tissue cross-reactivity characteristics with a comprehensive summary of what has already been performed in preclinical models to evaluate imaging and therapeutic activities. A molecular dynamics study was performed, and ScFvD2B occupied a limited conformational space, characterized by low-energy conformational basins, confirming the high stability of the protein structure. In the cross-reactivity study, the weak/absent immunoreactivity in non-tumor tissues was comparable to the PSMA expression reported in the literature. Biodistribution studies and therapeutic treatments were conducted in different animal models obtained by subcutaneous or locoregional injection of PSMA-positive-versus-negative xenografts. The maximum tumor uptake was observed for
123 I(SPECT),124 I(PET), and optical imaging, which avoids kidney accumulation (compared with radiometals) and leads to an optimal tumor-to-kidney and tumor-to-background ratios. Regarding its possible use in therapy, experimental data suggested a strong and specific antitumor activity, in vitro and in vivo, obtained using CAR-T or NK-92/CAR cells expressing scFvD2B. Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment.- Published
- 2021
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39. A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer.
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Bertolini G, Cancila V, Milione M, Lo Russo G, Fortunato O, Zaffaroni N, Tortoreto M, Centonze G, Chiodoni C, Facchinetti F, Pollaci G, Taiè G, Giovinazzo F, Moro M, Camisaschi C, De Toma A, D'Alterio C, Pastorino U, Tripodo C, Scala S, Sozzi G, and Roz L
- Subjects
- A549 Cells, Animals, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, Cisplatin pharmacology, Drug Interactions, Humans, Lung Neoplasms immunology, Male, Mice, Neoplasm Metastasis, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells immunology, Peptides pharmacology, RAW 264.7 Cells, Receptors, CXCR4 antagonists & inhibitors, Xenograft Model Antitumor Assays, AC133 Antigen metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Chemokine CXCL12 metabolism, Cisplatin administration & dosage, Lung Neoplasms drug therapy, Monocytes metabolism, Peptides administration & dosage, Receptors, CXCR4 metabolism
- Abstract
Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2
+ CXCR4+ Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+ CXCR4+ metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+ CXCR4+ IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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40. Back to simplicity: a four-marker blood cell score to quantify prognostically relevant myeloid cells in melanoma patients.
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Huber V, Di Guardo L, Lalli L, Giardiello D, Cova A, Squarcina P, Frati P, Di Giacomo AM, Pilla L, Tazzari M, Camisaschi C, Arienti F, Castelli C, Rodolfo M, Beretta V, Di Nicola M, Maio M, Del Vecchio M, de Braud F, Mariani L, and Rivoltini L
- Subjects
- Case-Control Studies, Humans, Lymphocyte Count, Machine Learning, Neoplasm Metastasis, Neutrophils metabolism, Prognosis, Survival Analysis, Biomarkers, Tumor blood, L-Lactate Dehydrogenase blood, Melanoma blood, Myeloid-Derived Suppressor Cells metabolism
- Abstract
Background: Myeloid-derived suppressor cells (MDSC), a cornerstone of cancer-related immunosuppression, influence response to therapy and disease outcomes in melanoma patients. Nevertheless, their quantification is far from being integrated into routine clinical practice mostly because of the complex and still evolving phenotypic signatures applied to define the cell subsets. Here, we used a multistep downsizing process to verify whether a core of few markers could be sufficient to capture the prognostic potential of myeloid cells in peripheral blood mononuclear cells (PBMC) of metastatic melanoma patients., Methods: In baseline frozen PBMC from a total of 143 stage IIIc to IV melanoma patients, we first assessed the relevant or redundant expression of myeloid and MDSC-related markers by flow cytometry (screening set, n=23 patients). Subsequently, we applied the identified panel to the development set samples (n=59 patients undergoing first/second-line therapy) to obtain prognostic variables associated with overall survival (OS) and progression-free survival (PFS) by machine learning adaptive index modeling. Finally, the identified score was confirmed in a validation set (n=61) and compared with standard clinical prognostic factors to assess its additive value in patient prognostication., Results: This selection process led to the identification of what we defined myeloid index score (MIS), which is composed by four cell subsets (CD14
+ , CD14+ HLA-DRneg , CD14+ PD-L1+ and CD15+ cells), whose frequencies above cut-offs stratified melanoma patients according to progressively worse prognosis. Patients with a MIS=0, showing no over-threshold value of MIS subsets, had the best clinical outcome, with a median survival of >33.6 months, while in patients with MIS 1→3, OS deteriorated from 10.9 to 6.8 and 6.0 months as the MIS increased (p<0.0001, c-index=0.745). MIS clustered patients into risk groups also according to PFS (p<0.0001). The inverse correlation between MIS and survival was confirmed in the validation set, was independent of the type of therapy and was not interfered by clinical prognostic factors. MIS HR was remarkably superior to that of lactate dehydrogenase, tumor burden and neutrophil-to-lymphocyte ratio., Conclusion: The MIS >0 identifies melanoma patients with a more aggressive disease, thus acting as a simple blood biomarker that can help tailoring therapeutic choices in real-life oncology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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41. Cyclophosphamide and Vinorelbine Activate Stem-Like CD8 + T Cells and Improve Anti-PD-1 Efficacy in Triple-Negative Breast Cancer.
- Author
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Falvo P, Orecchioni S, Hillje R, Raveane A, Mancuso P, Camisaschi C, Luzi L, Pelicci P, and Bertolini F
- Subjects
- Animals, Antigen-Presenting Cells drug effects, Antigen-Presenting Cells immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, CD8-Positive T-Lymphocytes immunology, Cell Adhesion, Female, Hepatocyte Nuclear Factor 1-alpha metabolism, Immunity, Cellular, Mice, Mice, Inbred BALB C, Transcriptome, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms immunology, Antineoplastic Agents pharmacology, CD8-Positive T-Lymphocytes drug effects, Cyclophosphamide pharmacology, Immune Checkpoint Inhibitors pharmacology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Triple Negative Breast Neoplasms drug therapy, Vinorelbine pharmacology
- Abstract
Checkpoint inhibitors (CI) instigate anticancer immunity in many neoplastic diseases, albeit only in a fraction of patients. The clinical success of cyclophosphamide (C)-based haploidentical stem-cell transplants indicates that this drug may re-orchestrate the immune system. Using models of triple-negative breast cancer (TNBC) with different intratumoral immune contexture, we demonstrate that a combinatorial therapy of intermittent C, CI, and vinorelbine activates antigen-presenting cells (APC), and abrogates local and metastatic tumor growth by a T-cell-related effect. Single-cell transcriptome analysis of >50,000 intratumoral immune cells after therapy treatment showed a gene signature suggestive of a change resulting from exposure to a mitogen, ligand, or antigen for which it is specific, as well as APC-to-T-cell adhesion. This transcriptional program also increased intratumoral Tcf1
+ stem-like CD8+ T cells and altered the balance between terminally and progenitor-exhausted T cells favoring the latter. Overall, our data support the clinical investigation of this therapy in TNBC. SIGNIFICANCE: A combinatorial therapy in mouse models of breast cancer increases checkpoint inhibition by activating antigen-presenting cells, enhancing intratumoral Tcf1+ stem-like CD8+ T cells, and increasing progenitor exhausted CD8+ T cells., (©2020 American Association for Cancer Research.)- Published
- 2021
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42. Efficacy of venetoclax based salvage chemotherapy followed by "Minimal Residual Disease driven"-venetoclax maintenance therapy post-allotransplant in a young patient with high risk primary refractory acute myeloid leukemia.
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Todisco E, Gigli F, Sammassimo S, Camisaschi C, Mancuso P, Ronchini C, Ramadan S, Bertolini F, Pastano R, and Tarella C
- Subjects
- Humans, Neoplasm, Residual, Sulfonamides therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Published
- 2020
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43. Natural-Killer-Derived Extracellular Vesicles: Immune Sensors and Interactors.
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Federici C, Shahaj E, Cecchetti S, Camerini S, Casella M, Iessi E, Camisaschi C, Paolino G, Calvieri S, Ferro S, Cova A, Squarcina P, Bertuccini L, Iosi F, Huber V, and Lugini L
- Subjects
- CD56 Antigen metabolism, Cell Line, Tumor, Cells, Cultured, DNA-Binding Proteins metabolism, Endosomal Sorting Complexes Required for Transport metabolism, Humans, Immunologic Surveillance, Immunomodulation, Melanoma diagnosis, Monitoring, Immunologic, NK Cell Lectin-Like Receptor Subfamily K metabolism, Protein Interaction Maps, Proteomics, Transcription Factors metabolism, Extracellular Vesicles pathology, Immunoassay methods, Killer Cells, Natural pathology, Leukocytes, Mononuclear immunology, Melanoma immunology
- Abstract
Natural killer (NK) cells contribute to immunosurveillance and first-line defense in the control of tumor growth and metastasis diffusion. NK-cell-derived extracellular vesicles (NKEVs) are constitutively secreted and biologically active. They reflect the protein and genetic repertoire of originating cells, and exert antitumor activity in vitro and in vivo . Cancer can compromise NK cell functions, a status potentially reflected by their extracellular vesicles. Hence, NKEVs could, on the one hand, contribute to improve cancer therapy by interacting with tumor and/or immune cells and on the other hand, sense the actual NK cell status in cancer patients. Here, we investigated the composition of healthy donors' NKEVs, including NK microvesicles and exosomes, and their interaction with uncompromised cells of the immune system. To sense the systemic NK cell status in cancer patients, we developed an immune enzymatic test (NKExoELISA) that measures plasma NK-cell-derived exosomes, captured as tsg101
+ CD56+ nanovesicles. NKEV mass spectrometry and cytokine analysis showed the expression of NK cell markers, i.e., NKG2D and CD94, perforin, granzymes, CD40L, and other molecules involved in cytotoxicity, homing, cell adhesion, and immune activation, together with EV markers tsg101, CD81, CD63, and CD9 in both NK-derived exosomes and microvesicles. Data are available via Proteome Xchange with identifier PXD014894. Immunomodulation studies revealed that NKEVs displayed main stimulatory functions in peripheral blood mononuclear cells (PBMCs), inducing the expression of human leukocyte antigen DR isotype (HLA-DR) and costimulatory molecules on monocytes and CD25 expression on T cells, which was maintained in the presence of lipopolysaccharide (LPS) and interleukin (IL)-10/transforming growth factor beta (TGFβ), respectively. Furthermore, NKEVs increased the CD56+ NK cell fraction, suggesting that effects mediated by NKEVs might be potentially exploited in support of cancer therapy. The measurement of circulating NK exosomes in the plasma of melanoma patients and healthy donors evidenced lower levels of tsg101+ CD56+ exosomes in patients with respect to donors. Likewise, we detected lower frequencies of NK cells in PBMCs of these patients. These data highlight the potential of NKExoELISA to sense alterations of the NK cell immune status., (Copyright © 2020 Federici, Shahaj, Cecchetti, Camerini, Casella, Iessi, Camisaschi, Paolino, Calvieri, Ferro, Cova, Squarcina, Bertuccini, Iosi, Huber and Lugini.)- Published
- 2020
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44. TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer.
- Author
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Bianchi F, Alexiadis S, Camisaschi C, Truini M, Centonze G, Milione M, Balsari A, Tagliabue E, and Sfondrini L
- Subjects
- Animals, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Caspase 3 immunology, Cell Line, Tumor, Humans, Immunity, Innate, Immunotherapy, Lung Neoplasms pathology, Lung Neoplasms therapy, Mice, Toll-Like Receptor 3 agonists, Apoptosis immunology, Carcinoma, Non-Small-Cell Lung immunology, Gene Expression Regulation, Neoplastic immunology, Lung Neoplasms immunology, Neoplasm Proteins immunology, Toll-Like Receptor 3 immunology
- Abstract
The prognostic value of Toll-like receptor 3 (TLR3) is debated in cancer, differing between tumor types, methods, and cell types. We recently showed for the first time that TLR3 expression on early stage non-small-cell lung cancer (NSCLC) results associated with a good prognosis. Here, we provide experimental evidences explaining the molecular reason behind TLR3's favorable prognostic role. We demonstrated that TLR3 activation in vitro induces apoptosis in lung cancer cell lines and, accordingly, that TLR3 expression is associated with caspase-3 activation in adenocarcinoma NSCLC specimens, both evaluated by immunohistochemistry. Moreover, we showed that TLR3 expression on cancer cells contributes to activate the CD103+ lung dendritic cell subset, that is specifically associated with processing of antigens derived from apoptotic cells and their presentation to CD8+ T lymphocytes. These findings point to the relevant role of TLR3 expression on lung cancer cells and support the use of TLR3 agonists in NSCLC patients to re-activate local innate immune response.
- Published
- 2020
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45. Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk.
- Author
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Fortunato O, Borzi C, Milione M, Centonze G, Conte D, Boeri M, Verri C, Moro M, Facchinetti F, Andriani F, Roz L, Caleca L, Huber V, Cova A, Camisaschi C, Castelli C, Cancila V, Tripodo C, Pastorino U, and Sozzi G
- Subjects
- Animals, Carcinogenesis immunology, Cell Line, Tumor, Circulating MicroRNA blood, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic immunology, Humans, Lung pathology, Lung Neoplasms blood, Lung Neoplasms genetics, Lung Neoplasms pathology, Macrophages metabolism, Male, Mice, Mice, SCID, MicroRNAs blood, Neutrophils immunology, Neutrophils metabolism, STAT4 Transcription Factor genetics, STAT4 Transcription Factor metabolism, Tobacco Smoking blood, Tobacco Smoking immunology, Xenograft Model Antitumor Assays, Circulating MicroRNA metabolism, Lung Neoplasms immunology, Macrophages immunology, MicroRNAs metabolism, Tumor Escape genetics
- Abstract
miRNAs play a central role in the complex signaling network of cancer cells with the tumor microenvironment. Little is known on the origin of circulating miRNAs and their relationship with the tumor microenvironment in lung cancer. Here, we focused on the cellular source and relative contribution of different cell types to circulating miRNAs composing our risk classifier of lung cancer using in vitro/in vivo models and clinical samples. A cell-type specific expression pattern and topography of several miRNAs such as mir-145 in fibroblasts, mir-126 in endothelial cells, mir-133a in skeletal muscle cells was observed in normal and lung cancer tissues. Granulocytes and platelets are the major contributors of miRNAs release in blood. miRNAs modulation observed in plasma of lung cancer subjects was consistent with de-regulation of the same miRNAs observed during immunosuppressive conversion of immune cells. In particular, activated neutrophils showed a miRNA profile mirroring that observed in plasma of lung cancer subjects. Interestingly mir-320a secreted by neutrophils of high-risk heavy-smokers promoted an M2-like protumorigenic phenotype through downregulation of STAT4 when shuttled into macrophages. These findings suggest a multifactorial and nonepithelial cell-autonomous origin of circulating miRNAs associated with risk of lung cancer and that circulating miRNAs may act in paracrine signaling with causative role in lung carcinogenesis and immunosuppression., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2019
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46. Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease.
- Author
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Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, Sanguinetti M, Morelli D, Paroni Sterbini F, Petito V, Reddel S, Calvani R, Camisaschi C, Picca A, Tuccitto A, Gasbarrini A, Pompili M, and Mazzaferro V
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Carcinoma, Hepatocellular congenital, Carcinoma, Hepatocellular microbiology, Gastrointestinal Microbiome, Inflammation complications, Liver Cirrhosis complications, Liver Neoplasms complications, Liver Neoplasms microbiology, Non-alcoholic Fatty Liver Disease complications
- Abstract
The gut-liver axis plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which is the third leading cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with cirrhosis and NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1, 21 patients), NAFLD-related cirrhosis without HCC (group 2, 20 patients), and healthy controls (group 3, 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status, and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, while intestinal permeability was similar to patients with cirrhosis but without HCC. Plasma levels of interleukin 8 (IL8), IL13, chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with cirrhosis showed higher abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides. Conclusion: Our results suggest that in patients with cirrhosis and NAFLD the gut microbiota profile and systemic inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis., (© 2018 by the American Association for the Study of Liver Diseases.)
- Published
- 2019
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47. Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types.
- Author
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Tazzari M, Brich S, Tuccitto A, Bozzi F, Beretta V, Spagnuolo RD, Negri T, Stacchiotti S, Deraco M, Baratti D, Camisaschi C, Villa A, Vergani B, Rivoltini L, Pilotti S, and Castelli C
- Subjects
- Adaptive Immunity, B7-H1 Antigen metabolism, Carcinogenesis, Humans, Immunohistochemistry, Immunosuppression Therapy, Lung Neoplasms pathology, Mesothelioma pathology, Mesothelioma, Malignant, Paraffin Embedding, Peritoneal Neoplasms pathology, Phenotype, Programmed Cell Death 1 Receptor metabolism, Tumor Escape, Tumor Microenvironment, B-Lymphocytes, Regulatory immunology, Enhancer of Zeste Homolog 2 Protein metabolism, Lung Neoplasms immunology, Lymphocytes, Tumor-Infiltrating immunology, Mesothelioma immunology, Peritoneal Neoplasms immunology, T-Lymphocytes, Regulatory immunology, Th1 Cells immunology
- Abstract
Malignant peritoneal mesothelioma (MpM), arising in the setting of local inflammation, is a rare aggressive tumour with a poor prognosis and limited therapeutic options. The three major MpM histological variants, epithelioid (E-MpMs), biphasic, and sarcomatoid MpMs (S-MpMs), are characterised by an increased aggressiveness and enhanced levels of EZH2 expression. To investigate the MpM immune contexture along the spectrum of MpM histotypes, an extended in situ analysis was performed on a series of 14 cases. Tumour-infiltrating immune cells and their functionality were assessed by immunohistochemistry, immunofluorescence, qRT-PCR, and flow cytometry analysis. MpMs are featured by a complex immune landscape modulated along the spectrum of MpM variants. Tumour-infiltrating T cells and evidence for pre-existing antitumour immunity are mainly confined to E-MpMs. However, Th1-related immunological features are progressively impaired in the more aggressive forms of E-MpMs and completely lost in S-MpM. Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1. This study enriches the rising rationale for immunotherapy in MpM and points to the E-MpMs as the most immune-sensitive MpM histotypes, but it also suggests that synergistic interventions aimed at modifying the tumour microenvironment (TME) should be considered to make immunotherapy beneficial for these patients.
- Published
- 2018
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48. Immune landscape and in vivo immunogenicity of NY-ESO-1 tumor antigen in advanced neuroblastoma patients.
- Author
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Camisaschi C, Renne SL, Beretta V, Rini F, Spagnuolo RD, Tuccitto A, Podda MG, Parmiani G, Rivoltini L, Collini P, Castelli C, and Luksch R
- Subjects
- Antigens, Neoplasm therapeutic use, Child, Preschool, Female, Humans, Immunotherapy, Active, Lymphocytes, Tumor-Infiltrating immunology, Membrane Proteins therapeutic use, Neuroblastoma pathology, T-Lymphocyte Subsets immunology, Antigens, Neoplasm immunology, Cancer Vaccines, Immunogenicity, Vaccine, Membrane Proteins immunology, Neuroblastoma immunology, Neuroblastoma therapy
- Abstract
Background: Indirect evidence suggesting the immunosensitivity/immunogenicity of neuroblastoma is accumulating. The aims of this study were to investigate the immune landscape of neuroblastoma and to evaluate the in vivo immunogenicity of the NY-ESO-1 tumor antigen in advanced neuroblastoma patients., Methods: The immune infiltrating cells of the NY-ESO-1+ tumors from three HLA*A201 patients with metastatic neuroblastoma who relapsed after conventional treatments were evaluated by immunohistochemistry. The patients were vaccinated with the HLA-A*0201-restricted peptide NY-ESO-1
157-165(V) . The peptide was emulsified in Montanide ISA51 and given subcutaneously in a phase I pilot study. The immunogenicity of NY-ESO-1 antigen was evaluated by monitoring mononuclear cells in patient peripheral blood, pre- and post-vaccine, by short-term in vitro sensitization, HLA-multimer staining and IFN-γ ELISpot analysis., Results: Both CD3 T cells and CD163 myeloid cells were present in pre-vaccine tumors and PD-1 and PD-L1 expression was mainly found in the immune infiltrate. Despite the advanced stage of the disease, the vaccination induced systemic NY-ESO-1 specific CD8 T cells releasing IFN-γ in response to activation with the NY-ESO-1 peptide and an HLA-A2 positive neuroblastoma cell line., Conclusions: Our results indicate that vaccination with a tumor-associated peptide is able to boost NY-ESO-1-specific, functionally active T cells in advanced neuroblastoma patients with lymphocyte infiltration in their pre-vaccine tumors., Trial Registration: EudraCT #2006-002859-33.- Published
- 2018
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49. Modulation of Pulmonary Microbiota by Antibiotic or Probiotic Aerosol Therapy: A Strategy to Promote Immunosurveillance against Lung Metastases.
- Author
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Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, Storti C, Triulzi T, Castelli C, Balsari A, Tagliabue E, and Sfondrini L
- Subjects
- Administration, Inhalation, Animals, Anti-Bacterial Agents administration & dosage, Cell Line, Tumor, Cells, Cultured, Female, Lung Neoplasms immunology, Lung Neoplasms microbiology, Lung Neoplasms secondary, Melanoma pathology, Mice, Mice, Inbred C57BL, Probiotics administration & dosage, Anti-Bacterial Agents therapeutic use, Immunologic Surveillance, Lung microbiology, Lung Neoplasms therapy, Microbiota, Probiotics therapeutic use
- Abstract
Pulmonary immunological tolerance to inhaled particulates might create a permissive milieu for lung metastasis. Lung microbiota contribute to pulmonary tolerance; here, we explored whether its manipulation via antibiotic or probiotic aerosolization favors immune response against melanoma metastasis. In lungs of vancomycin/neomycin-aerosolized mice, a decrease in bacterial load was associated with reduced regulatory T cells and enhanced T cell and NK cell activation that paralleled a significant reduction of melanoma B16 lung metastases. Reduction of metastases also occurred in lungs transplanted with bacterial isolates from antibiotic-treated lungs. Aerosolized Lactobacillus rhamnosus strongly promoted immunity against B16 lung metastases as well. Furthermore, probiotics or antibiotics improved chemotherapy activity against advanced B16 metastases. Thus, we identify a role for lung microbiota in metastasis and show that its targeting via aerosolization is a therapy that can prevent metastases and enhance responses to chemotherapy., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
50. pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma.
- Author
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Kuchuk O, Tuccitto A, Citterio D, Huber V, Camisaschi C, Milione M, Vergani B, Villa A, Alison MR, Carradori S, Supuran CT, Rivoltini L, Castelli C, and Mazzaferro V
- Abstract
Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking ex vivo V-ATPase activity established a less immune-suppressive tumor microenvironment and reversed the mesenchymal features of HCC. Thus, targeting the unique cross-talk between tumor cells and the tumor microenvironment played by pH regulatory molecules holds promise as a strategy to control HCC progression and to reduce the immunosuppressive pressure mediated by the hypoxic/acidic metabolism, particularly considering the potential combination of this strategy with emerging immune checkpoint-based immunotherapies.
- Published
- 2018
- Full Text
- View/download PDF
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