18 results on '"Kleffel S"'
Search Results
2. Improved Function of Circulating Angiogenic Cells Is Evident in Type 1 Diabetic Islet-Transplanted Patients
- Author
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Petrelli, A., Maestroni, A., Fadini, G.P., Belloni, D., Venturi, M., Albero, M., Kleffel, S., Mfarrej, B.G., Del Maschio, A., Maffi, P., Avogaro, A., Ferrero, E., Zerbini, G., Secchi, A., and Fiorina, P.
- Published
- 2010
- Full Text
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3. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
- Author
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Kleffel, S., Posch, C., Barthel, S.R., Mueller, H., Schlapbach, C., Guenova, E., Elco, C.P., Lee, N., Juneja, V.R., Zhan, Q., Lian, C.G., Thomi, R., Hoetzenecker, W., Cozzio, A., Dummer, R., Mihm, M.C., Jr, Flaherty, Kieth T., Murphy, G.F., Sharpe, A.H., Kupper, T.S., Schatton, T., Kleffel, S., Posch, C., Barthel, S.R., Mueller, H., Schlapbach, C., Guenova, E., Elco, C.P., Lee, N., Juneja, V.R., Zhan, Q., Lian, C.G., Thomi, R., Hoetzenecker, W., Cozzio, A., Dummer, R., Mihm, M.C., Jr, Flaherty, Kieth T., Murphy, G.F., Sharpe, A.H., Kupper, T.S., and Schatton, T.
- Abstract
Summary Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.
- Published
- 2015
4. Combined inhibition of MEK and Plk1 has synergistic anti-tumor activity in NRAS mutant melanoma
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Posch, C, Cholewa, BD, Vujic, I, Sanlorenzo, M, Ma, J, Kim, ST, Kleffel, S, Schatton, T, Rappersberger, K, Gutteridge, R, Ahmad, N, and Ortiz/Urda, S
- Abstract
About one third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS driven malignancies barely impact overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Plk1 expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of MEK and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo and first mechanistic data, that a MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS driven melanoma. Since mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins.
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- 2015
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5. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
- Author
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Kleffel, S., Posch, C., Barthel, S.R., Mueller, H., Schlapbach, C., Guenova, E., Elco, C.P., Lee, N., Juneja, V.R., Zhan, Q., Lian, C.G., Thomi, R., Hoetzenecker, W., Cozzio, A., Dummer, R., Mihm, M.C., Jr, Flaherty, Kieth T., Murphy, G.F., Sharpe, A.H., Kupper, T.S., Schatton, T., Kleffel, S., Posch, C., Barthel, S.R., Mueller, H., Schlapbach, C., Guenova, E., Elco, C.P., Lee, N., Juneja, V.R., Zhan, Q., Lian, C.G., Thomi, R., Hoetzenecker, W., Cozzio, A., Dummer, R., Mihm, M.C., Jr, Flaherty, Kieth T., Murphy, G.F., Sharpe, A.H., Kupper, T.S., and Schatton, T.
- Abstract
Kleffel, S., Posch, C., Barthel, et al. (2015). Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth in Cell, 162(6), 1242-1256. Available here.
6. Improved Function of Circulating Angiogenic Cells Is Evident in Type 1 Diabetic Islet-Transplanted Patients
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Gianpaolo Zerbini, Bechara Mfarrej, Paola Maffi, M. Venturini, Daniela Belloni, Anna Maestroni, Sonja Kleffel, Angelo Avogaro, Elisabetta Ferrero, A. Del Maschio, Paolo Fiorina, Alessandra Petrelli, Antonio Secchi, Gian Paolo Fadini, Mattia Albiero, Petrelli, A, Maestroni, A, Fadini, Gp, Belloni, D, Venturini, M, Albiero, M, Kleffel, S, Mfarrej, Bg, Maschio, Ad, Maffi, P, Avogaro, A, Ferrero, E, Zerbini, G, Secchi, Antonio, and Fiorina, P.
- Subjects
Adult ,Blood Glucose ,Male ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Angiogenesis ,medicine.medical_treatment ,Islets of Langerhans Transplantation ,Neovascularization, Physiologic ,Apoptosis ,Neovascularization ,Islets of Langerhans ,immune system diseases ,In vivo ,Internal medicine ,medicine ,Humans ,Insulin ,Immunology and Allergy ,Pharmacology (medical) ,Interleukin 8 ,Cell Proliferation ,Ultrasonography ,bcl-2-Associated X Protein ,Transplantation ,geography ,Type 1 diabetes ,geography.geographical_feature_category ,business.industry ,Interleukin-8 ,nutritional and metabolic diseases ,Islet ,medicine.disease ,Diabetes Mellitus, Type 1 ,Cytokine ,Endocrinology ,Female ,bcl-Associated Death Protein ,Endothelium, Vascular ,medicine.symptom ,business - Abstract
Objectives- Circulating angiogenic cells (CACs) are vascular-committed bone-marrow derived cells expressing endothelial and stem cell markers that are dysfunctional in type 1 diabetes (T1D). We studied if restoration of endogenous beta cells function with islet transplantation is associated with better CACs function. Research design and methods- 18 T1D patients, 14 insulin independent islet-transplanted patients (ITA) and 14 healthy controls (C) were studied cross-sectionally. In vivo (CACs percentage/apoptosis and migratory/differentiation assay) and in vitro studies [colony forming unit endothelial cells (CFU-ECs) counting, CACs percentage/apoptosis, cytokine production and migratory/differentiation assay] were performed, together with endothelial dependent dilatation (EDD) test in vivo. The addition of serial concentrations IL-8 and anti-IL8 in vitro cultures was performed to assess IL-8 mediated cell survival/apoptosis. Results- The percentage of alive and apoptotic CACs did not differ among the 3 groups. CFU-ECs absolute number obtained from T1D, but not from ITA, was reduced compared to C (C=7.3±1.9, T1D=0.9±0.4 and ITA=4.7±1.9; p
- Published
- 2010
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7. Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.
- Author
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Martins C, Rasbach E, Heppt MV, Singh P, Kulcsar Z, Holzgruber J, Chakraborty A, Mucciarone K, Kleffel S, Brandenburg A, Hoetzenecker W, Rahbari NN, DeCaprio JA, Thakuria M, Murphy GF, Ramsey MR, Posch C, Barthel SR, and Schatton T
- Subjects
- Humans, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Reactive Oxygen Species, TOR Serine-Threonine Kinases, Carcinoma, Merkel Cell drug therapy, Carcinoma, Merkel Cell genetics, Skin Neoplasms drug therapy, Skin Neoplasms genetics
- Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.
- Published
- 2024
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8. ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth.
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Kleffel S, Lee N, Lezcano C, Wilson BJ, Sobolewski K, Saab KR, Mueller H, Zhan Q, Posch C, Elco CP, DoRosario A, Garcia SS, Thakuria M, Wang YE, Wang LC, Murphy GF, Frank MH, and Schatton T
- Subjects
- ATP Binding Cassette Transporter, Subfamily B metabolism, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Animals, Antineoplastic Agents administration & dosage, Carboplatin administration & dosage, Carcinoma, Merkel Cell drug therapy, Cell Line, Tumor, Cell Proliferation drug effects, Etoposide administration & dosage, Flow Cytometry, Humans, Immunohistochemistry, Interleukin Receptor Common gamma Subunit genetics, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Multidrug Resistance-Associated Proteins metabolism, Neoplasm Transplantation, Real-Time Polymerase Chain Reaction, Skin metabolism, Skin Neoplasms drug therapy, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Carcinoma, Merkel Cell metabolism, Drug Resistance, Neoplasm, Skin Neoplasms metabolism
- Abstract
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin- and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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9. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.
- Author
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Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, Elco CP, Lee N, Juneja VR, Zhan Q, Lian CG, Thomi R, Hoetzenecker W, Cozzio A, Dummer R, Mihm MC Jr, Flaherty KT, Frank MH, Murphy GF, Sharpe AH, Kupper TS, and Schatton T
- Subjects
- Animals, Antineoplastic Agents administration & dosage, B7-H1 Antigen genetics, Cell Line, Tumor, Cells, Cultured, Gene Knockdown Techniques, Heterografts, Humans, Mice, Mice, Inbred C57BL, Neoplasm Transplantation, Melanoma genetics, Programmed Cell Death 1 Receptor metabolism, Signal Transduction
- Abstract
Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
10. ABCB5 Identifies Immunoregulatory Dermal Cells.
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Schatton T, Yang J, Kleffel S, Uehara M, Barthel SR, Schlapbach C, Zhan Q, Dudeney S, Mueller H, Lee N, de Vries JC, Meier B, Vander Beken S, Kluth MA, Ganss C, Sharpe AH, Waaga-Gasser AM, Sayegh MH, Abdi R, Scharffetter-Kochanek K, Murphy GF, Kupper TS, Frank NY, and Frank MH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Allografts, Animals, Biomarkers metabolism, Cell Proliferation, Cells, Cultured, Dermis cytology, Graft Survival, Heart Transplantation, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, T-Lymphocytes immunology, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, T-Lymphocytes, Regulatory physiology
- Abstract
Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5(+) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5(+) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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11. Interleukin-10+ regulatory B cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens.
- Author
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Kleffel S, Vergani A, Tezza S, Ben Nasr M, Niewczas MA, Wong S, Bassi R, D'Addio F, Schatton T, Abdi R, Atkinson M, Sayegh MH, Wen L, Wasserfall CH, O'Connor KC, and Fiorina P
- Subjects
- Adult, Animals, Autoantigens genetics, Autoantigens immunology, B-Lymphocytes, Regulatory metabolism, CD40 Antigens metabolism, Female, Humans, Interleukin-10 metabolism, Male, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Middle Aged, Transcriptome immunology, Young Adult, B-Lymphocytes, Regulatory immunology, CD40 Antigens immunology, Diabetes Mellitus, Type 1 immunology, Immune Tolerance immunology, Interleukin-10 immunology, Islets of Langerhans immunology
- Abstract
Impaired regulatory B cell (Breg) responses are associated with several autoimmune diseases in humans; however, the role of Bregs in type 1 diabetes (T1D) remains unclear. We hypothesized that naturally occurring, interleukin-10 (IL-10)-producing Bregs maintain tolerance to islet autoantigens, and that hyperglycemic nonobese diabetic (NOD) mice and T1D patients lack these potent negative regulators. IgVH transcriptome analysis revealed that islet-infiltrating B cells in long-term normoglycemic (Lnglc) NOD, which are naturally protected from diabetes, are more antigen-experienced and possess more diverse B-cell receptor repertoires compared to those of hyperglycemic (Hglc) mice. Importantly, increased levels of Breg-promoting CD40(+) B cells and IL-10-producing B cells were found within islets of Lnglc compared to Hglc NOD. Likewise, healthy individuals showed increased frequencies of both CD40(+) and IL-10(+) B cells compared to T1D patients. Rituximab-mediated B-cell depletion followed by adoptive transfer of B cells from Hglc mice induced hyperglycemia in Lnglc human CD20 transgenic NOD mouse models. Importantly, both murine and human IL-10(+) B cells significantly abrogated T-cell-mediated responses to self- or islet-specific peptides ex vivo. Together, our data suggest that antigen-matured Bregs may maintain tolerance to islet autoantigens by selectively suppressing autoreactive T-cell responses, and that Hglc mice and individuals with T1D lack this population of Bregs., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Published
- 2015
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12. Nestin depletion induces melanoma matrix metalloproteinases and invasion.
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Lee CW, Zhan Q, Lezcano C, Frank MH, Huang J, Larson AR, Lin JY, Wan MT, Lin PI, Ma J, Kleffel S, Schatton T, Lian CG, and Murphy GF
- Subjects
- Animals, Cell Line, Tumor, Female, Focal Adhesion Protein-Tyrosine Kinases metabolism, Humans, Mice, Neoplasm Invasiveness, Transforming Growth Factor beta physiology, Matrix Metalloproteinases physiology, Melanoma pathology, Nestin physiology
- Abstract
Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase and increased melanoma cell responsiveness to transforming growth factor-beta, both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.
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- 2014
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13. Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts.
- Author
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Lezcano C, Kleffel S, Lee N, Larson AR, Zhan Q, DoRosario A, Wang LC, Schatton T, and Murphy GF
- Subjects
- Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Phytogenic therapeutic use, Carboplatin therapeutic use, Carcinoma, Merkel Cell drug therapy, Cell Line, Tumor, Etoposide therapeutic use, Human Umbilical Vein Endothelial Cells, Humans, Mice, Knockout, Middle Aged, Neoplasm Invasiveness, Neoplasm Transplantation, Random Allocation, Skin Neoplasms drug therapy, Transplantation, Heterologous, Carcinoma, Merkel Cell pathology, Lymph Nodes pathology, Neovascularization, Pathologic, Skin pathology, Skin Neoplasms pathology
- Abstract
Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents.
- Published
- 2014
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14. Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7.
- Author
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Vergani A, Tezza S, D'Addio F, Fotino C, Liu K, Niewczas M, Bassi R, Molano RD, Kleffel S, Petrelli A, Soleti A, Ammirati E, Frigerio M, Visner G, Grassi F, Ferrero ME, Corradi D, Abdi R, Ricordi C, Sayegh MH, Pileggi A, and Fiorina P
- Subjects
- Adenosine Triphosphate pharmacology, Adult, Animals, Chronic Disease, Disease Models, Animal, Female, Graft Rejection immunology, Heart Transplantation immunology, Humans, Immunocompetence drug effects, Immunocompetence immunology, Isoantigens immunology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Receptors, Purinergic P2X7 genetics, Receptors, Purinergic P2X7 immunology, STAT3 Transcription Factor metabolism, Survivors statistics & numerical data, Th1 Cells drug effects, Th1 Cells immunology, Th17 Cells drug effects, Th17 Cells immunology, Adenosine Triphosphate analogs & derivatives, Graft Rejection drug therapy, Graft Rejection mortality, Heart Transplantation mortality, Purinergic P2X Receptor Antagonists pharmacology, Receptors, Purinergic P2X7 metabolism
- Abstract
Background: Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine ATP, released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T-cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation., Methods and Results: We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T-cell activation, T-helper cell 1/T-helper cell 17 differentiation, and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well., Conclusions: P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.
- Published
- 2013
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15. Tumor dormancy and cancer stem cells: two sides of the same coin?
- Author
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Kleffel S and Schatton T
- Subjects
- Antineoplastic Agents pharmacology, Cell Communication, Cell Cycle Checkpoints, Cell Death, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic pathology, Combined Modality Therapy methods, Disease Progression, Drug Resistance, Neoplasm, Humans, Neoplasm Metastasis immunology, Neoplasm Metastasis pathology, Neoplasm Metastasis therapy, Neoplasm Recurrence, Local blood supply, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local therapy, Neoplasm, Residual immunology, Neoplasm, Residual pathology, Neoplasm, Residual therapy, Neoplastic Stem Cells immunology, Neovascularization, Pathologic immunology, Neovascularization, Pathologic pathology, Neovascularization, Pathologic therapy, Signal Transduction, Tumor Escape, Tumor Microenvironment, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells pathology
- Abstract
Increasing evidence suggests that tumor dormancy represents an important mechanism underlying the observed failure of existing therapeutic modalities to fully eradicate cancers. In addition to its more established role in maintaining minimal residual disease after treatment, dormancy might also critically contribute to early stages of tumor development and the formation of clinically undetectable micrometastatic foci. There are striking parallels between the concept of tumor dormancy and the cancer stem cell (CSC) theory of tumor propagation. For instance, the CSC hypothesis similarly predicts that a subset of self-renewing cancer cells-that is CSCs-is responsible for tumor initiation, bears the preferential ability to survive tumor therapy, and persists long term to ultimately cause delayed cancer recurrence and metastatic progression. Additionally, many of the biological mechanisms involved in controlling the dormant state of a tumor can also govern CSC behavior, including cell cycle modifications, alteration of angiogenic processes, and modulation of antitumor immune responses. In fact, quiescence and immune escape are emerging hallmark features of at least some CSCs, indicating significant overlap between dormant cancer populations and CSCs. Herein, we crucially dissect whether CSCs occupy specific roles in orchestrating the switch between dormancy and exuberant tumor growth. We elucidate how recently uncovered CSC biological features could enable these cells to evade immunologic clearance and regulate cancer expansion, relapse, and progression. We propose that the study of CSC immunobiological pathways holds the promise to critically advance our understanding of the processes mediating tumor dormancy. Ultimately, such research endeavors could unravel novel therapeutic avenues that efficiently target both proliferating and dormant CSCs to minimize the risk of tumor recurrence in cancer patients.
- Published
- 2013
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16. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.
- Author
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Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q, Lee CW, Hu D, Lian BQ, Kleffel S, Yang Y, Neiswender J, Khorasani AJ, Fang R, Lezcano C, Duncan LM, Scolyer RA, Thompson JF, Kakavand H, Houvras Y, Zon LI, Mihm MC Jr, Kaiser UB, Schatton T, Woda BA, Murphy GF, and Shi YG
- Subjects
- 5-Methylcytosine analogs & derivatives, Cytosine metabolism, DNA-Binding Proteins genetics, Dioxygenases, Genome-Wide Association Study, Humans, Isocitrate Dehydrogenase genetics, Melanocytes metabolism, Melanoma pathology, Nevus pathology, Proto-Oncogene Proteins genetics, Cytosine analogs & derivatives, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Melanoma genetics, Nevus genetics
- Abstract
DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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17. Modified CD4(+) T-cell response in recipients of old cardiac allografts.
- Author
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Denecke C, Ge X, Jurisch A, Kleffel S, Kim IK, Padera RF, Weiland A, Fiorina P, Pratschke J, and Tullius SG
- Subjects
- Age Factors, Animals, Enzyme-Linked Immunospot Assay, Flow Cytometry, Mice, Mice, Inbred C57BL, T-Lymphocytes, Regulatory metabolism, Time Factors, Transplantation, Homologous immunology, CD4-Positive T-Lymphocytes metabolism, Graft Survival immunology, Heart Transplantation immunology, Lymphocyte Activation
- Abstract
With an increasing demand, organs from elderly donors are more frequently utilized for transplantation. Herein, we analyzed the impact of donor age on CD4(+) T-cell responses with regard to regulatory and effector mechanisms. Young (3months) BM12 recipients were engrafted with young or old (18months) B6 cardiac allografts. Systemic CD4(+) T-cell responses and intragraft changes were monitored and compared to age-matched syngenic transplant controls. While elderly, nonmanipulated hearts contained significantly elevated frequencies of donor-derived leukocytes prior to transplantation, allograft survival was age-independent. T-cell activation, however, was delayed and associated with a compromised immune response in mixed lymphocyte cultures (MLR; P=0.0002) early after transplantation (day 14). During the time course after transplantation, recipients of old grafts demonstrated an augmented immune response as shown by significantly higher frequencies of activated CD4(+) T-cells and a stronger in vitro alloreactivity (MLR; ELISPOT; P<0.01). In parallel, frequencies of regulatory T-cells had increased systemically and overall fewer CD4(+) T-cells were detected intragraft. Interestingly, changes in the CD4(+) T-cell response were not reflected by graft morphology. Of note, transplantation of young and old syngenic hearts did not show age-related differences of the CD4(+) T-cells response suggesting that old grafts can recover from a period of short cold ischemia time. Our data suggest that donor age is associated with an augmented CD4(+) T-cells response which did not affect graft survival in our model. These findings contribute to a better understanding of the immune response following the engraftment of older donor organs., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)
- Published
- 2012
- Full Text
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18. IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response.
- Author
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Petrelli A, Carvello M, Vergani A, Lee KM, Tezza S, Du M, Kleffel S, Chengwen L, Mfarrej BG, Hwu P, Secchi A, Leonard WJ, Young D, Sayegh MH, Markmann JF, Zajac AJ, and Fiorina P
- Subjects
- Animals, Antibodies pharmacology, Apoptosis drug effects, B-Lymphocytes immunology, B-Lymphocytes metabolism, CD28 Antigens immunology, CD28 Antigens metabolism, CD3 Complex immunology, CD3 Complex metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cytokines, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Mice, Mice, Transgenic, Receptors, Interleukin-21 genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Interleukins metabolism, Receptors, Interleukin-21 metabolism
- Abstract
Objective: Interleukin-21 (IL-21) is a proinflammatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear., Research Design and Methods: The interplay between IL-21/IL-21R signaling, FoxP3 expression, and Treg survival and function was evaluated in vitro in immunologically relevant assays and in vivo in allogenic and autoimmune models of islet transplantation., Results: IL-21R expression decreases on T cells and B cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/anti-CD28 stimulation/allostimulation in the late phase of the alloimmune response. In vitro, IL-21/IL-21R signaling (by using rmIL-21 or genetically modified CD4(+) T cells [IL-21 pOrf plasmid-treated or hIL-21-Tg mice]) enhances the T-cell response during anti-CD3/anti-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis, and reduces FoxP3 and FoxP3-dependent gene transcripts without affecting FoxP3 methylation status. In vivo targeting of IL-21/IL-21R expands intragraft and peripheral Tregs, promotes Treg neogenesis, and regulates the antidonor immune response, whereas IL-21/IL-21R signaling in Doxa-inducible ROSA-rtTA-IL-21-Tg mice expands Teffs and FoxP3(-) cells. Treatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response) leads to robust graft tolerance in a purely alloimmune setting and prolonged islet graft survival in NOD mice., Conclusions: IL-21 interferes with different checkpoints of the FoxP3 Treg chain in the late phase of alloimmune response and, thus, acts as an antitolerogenic cytokine. Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation.
- Published
- 2011
- Full Text
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