23 results on '"Uranga Murillo, Iratxe"'
Search Results
2. Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality
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Albert, Marie-Christine, Uranga-Murillo, Iratxe, Arias, Maykel, De Miguel, Diego, Peña, Natacha, Montinaro, Antonella, Varanda, Ana Beatriz, Theobald, Sebastian J., Areso, Itziar, Saggau, Julia, Koch, Manuel, Liccardi, Gianmaria, Peltzer, Nieves, Rybniker, Jan, Hurtado-Guerrero, Ramón, Merino, Pedro, Monzón, Marta, Badiola, Juan J., Reindl-Schwaighofer, Roman, Sanz-Pamplona, Rebeca, Cebollada-Solanas, Alberto, Megyesfalvi, Zsolt, Dome, Balazs, Secrier, Maria, Hartmann, Boris, Bergmann, Michael, Pardo, Julián, and Walczak, Henning more...
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- 2024
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3. Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung
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Moreo, Eduardo, Jarit-Cabanillas, Aitor, Robles-Vera, Iñaki, Uranga, Santiago, Guerrero, Claudia, Gómez, Ana Belén, Mata-Martínez, Pablo, Minute, Luna, Araujo-Voces, Miguel, Felgueres, María José, Esteso, Gloria, Uranga-Murillo, Iratxe, Arias, Maykel, Pardo, Julián, Martín, Carlos, Valés-Gómez, Mar, del Fresno, Carlos, Sancho, David, and Aguiló, Nacho more...
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- 2023
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4. Ultrastructural analysis and three-dimensional reconstruction of cellular structures involved in SARS-CoV-2 spread
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Baselga, Marta, Moreo, Eduardo, Uranga-Murillo, Iratxe, Arias, Maykel, and Junquera, Concepción
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- 2023
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5. Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation
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Santiago, Llipsy, Castro, Marta, Sanz-Pamplona, Rebeca, Garzón, Marcela, Ramirez-Labrada, Ariel, Tapia, Elena, Moreno, Víctor, Layunta, Elena, Gil-Gómez, Gabriel, Garrido, Marta, Peña, Raúl, Lanuza, Pilar M., Comas, Laura, Jaime-Sanchez, Paula, Uranga-Murillo, Iratxe, del Campo, Rosa, Pelegrín, Pablo, Camerer, Eric, Martínez-Lostao, Luis, Muñoz, Guillermo, Uranga, José A., Alcalde, Anabel, Galvez, Eva M., Ferrandez, Angel, Bird, Phillip I., Metkar, Sunil, Arias, Maykel A., and Pardo, Julian more...
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- 2020
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6. Antigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance
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Jaime-Sánchez, Paula, Catalán, Elena, Uranga-Murillo, Iratxe, Aguiló, Nacho, Santiago, Llipsy, M Lanuza, Pilar, de Miguel, Diego, A Arias, Maykel, and Pardo, Julián
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- 2018
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7. Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis
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Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Seral, Cristina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-6630], Ushakova, Tatiana Khaliulina [0000-0002-7930-2129], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], and Pardo, Julián [0000-0003-0154-0730] more...
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Granzyme ,natural sciences ,Peritoneal sepsis ,Biomarkers - Abstract
of the work presented at the 30th ECCMID 2020, European Congress of Clinical Microbiology and Infectious Diseases, organized by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).-- www.eccmid.org .-- www.escmid.org.-- Accepted abstract 1508., [Background] Peritonitis is one of the most common leading cause of sepsis. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed in NK cells and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role of serum GzmA as a biomarker and therapeutic target in peritoneal sepsis., [Materials/methods] Concentration and enzyme activity of soluble GzmA were sequentially analyzed in serum from healthy donors and patients with peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (Wt) and GzmA-KO mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics and with serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days and the levels of serum proinflammatory cytokines and bacterial load in blood and spleen were analyzed at 6 and 24h from CLP., [Results] We have found high levels of GzmA in serum of patient with peritonitis. Most importantly, we observed that GzmA activity in serum correlates with SOFA score, suggesting that active GzmA could play an important role in sepsis development in peritonitis patients and could be a new biomarker of sepsis severity. In order to analyze the therapeutical potential of soluble GzmA in peritoneal sepsis, we used the CLP mouse model. After peritonitis induction, GzmA-KO mice exhibit increased survival compared with Wt mice, which correlated with reduced levels of proinflammatory cytokines in serum. The analysis of bacterial load in blood and spleen showed no differences between Wt and GzmA-KO mice suggesting that GzmA does not play an important role in bacterial control. Treatment with serpinb6b reduced mortality, which correlated with reduced cytokine serum levels in serum, confirming the therapeutical potential of gzmA to treat peritoneal sepsis., [Conclusions] Our findings confirm that soluble GzmA plays an important role in the pathogenesis of sepsis and could be a new therapeutic target and a biomarker for the treatment of peritoneal sepsis. more...
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- 2020
8. Concentration of IgG against the Spike Receptor-Binding Domain predicts the viral neutralization activity of convalescent plasma and serum against SARS-CoV-2
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Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, Moreo, Eduardo, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Paño, José Ramón, and Pardo, Julián
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Coronavirus ,Convalescent plasma ,SARS-CoV-2 ,IgG ,ELISA ,Antibodies - Abstract
Poster presentado en el 42º SEI Congreso de la Sociedad Española de Inmunología, 24-26 marzo 2021, Madrid, formato virtual., SARS-CoV-2 is the virus responsible for the Covid-19 pandemic, due to its rapid propagation and the initial lack of vaccines or appropriate treatments. Nowadays, despite different vaccines available, the main treatments are palliative, focused on supplemental oxygen and anti-inflammatory therapy. Passive immunization could be an effective and economic treatment once standarized. It consists of the transfer of pathogen-specific antibodies to patients whose immune system has not originated a response yet. The donors’ antibodies neutralize and attenuate pathogen replication. Besides, an antibody against the Receptor-Binding Domain of Spike (RBD) would block the interaction of the virus with ACE2 and its entry in the cell. Here, an in-house RBG IgG ELISA test has been validated using a cohort of more than 320 samples of convalescent plasma and serum and adapted to quantify the concentration of plasma RBD IgG and its correlation with the SARS-CoV-2 neutralizing activity in vitro. more...
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- 2021
9. TIM3, LAG3, CXCL10 and GzmA reveal as main hallmarks of inflammatory profiles in Covid-19 patiens
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Hidalgo, Sandra, Morte Romea, Elena, Pesini, Cecilia, Uranga Murillo, Iratxe, Sierra Monzón, José L., Martínez Lázaro, Beatriz, Paño, José Ramón, Gálvez Buerba, Eva Mª, and Pardo, Julián
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Inflammation ,Immune ,SARS-CoV-2 ,CXCL10 ,Granzyme A ,COVID-19 ,TIM3 ,Cytokine ,LAG3 - Abstract
Comunicación oral presentada en el 42º SEI Congreso de la Sociedad Española de Inmunología, 24-26 marzo 2021, Madrid, formato virtual.
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- 2021
10. Silver Nanoparticles–Polyethyleneimine-Based Coatings with Antiviral Activity against SARS-CoV-2: A New Method to Functionalize Filtration Media.
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Baselga, Marta, Uranga-Murillo, Iratxe, de Miguel, Diego, Arias, Maykel, Sebastián, Victor, Pardo, Julián, and Arruebo, Manuel
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SARS-CoV-2 , *SILVER nanoparticles , *SILVER , *SURFACE coatings , *AIR filters , *AIR purification , *MICROBIOLOGICAL aerosols , *POLYETHYLENEIMINE - Abstract
The use of face masks and air purification systems has been key to curbing the transmission of SARS-CoV-2 aerosols in the context of the current COVID-19 pandemic. However, some masks or air conditioning filtration systems are designed to remove large airborne particles or bacteria from the air, being limited their effectiveness against SARS-CoV-2. Continuous research has been aimed at improving the performance of filter materials through nanotechnology. This article presents a new low-cost method based on electrostatic forces and coordination complex formation to generate antiviral coatings on filter materials using silver nanoparticles and polyethyleneimine. Initially, the AgNPs synthesis procedure was optimized until reaching a particle size of 6.2 ± 2.6 nm, promoting a fast ionic silver release due to its reduced size, obtaining a stable colloid over time and having reduced size polydispersity. The stability of the binding of the AgNPs to the fibers was corroborated using polypropylene, polyester-viscose, and polypropylene-glass spunbond mats as substrates, obtaining very low amounts of detached AgNPs in all cases. Under simulated operational conditions, a material loss less than 1% of nanostructured silver was measured. SEM micrographs demonstrated high silver distribution homogeneity on the polymer fibers. The antiviral coatings were tested against SARS-CoV-2, obtaining inactivation yields greater than 99.9%. We believe our results will be beneficial in the fight against the current COVID-19 pandemic and in controlling other infectious airborne pathogens. [ABSTRACT FROM AUTHOR] more...
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- 2022
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11. Adoptive NK Cell Transfer as a Treatment in Colorectal Cancer Patients: Analyses of Tumour Cell Determinants Correlating With Efficacy In Vitro and In Vivo.
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Lanuza, Pilar M., Alonso, M. Henar, Hidalgo, Sandra, Uranga-Murillo, Iratxe, García-Mulero, Sandra, Arnau, Raquel, Santos, Cristina, Sanjuan, Xavier, Santiago, Llipsy, Comas, Laura, Redrado, Sergio, Pazo-Cid, Roberto, Agustin-Ferrández, M. Jose, Jaime-Sánchez, Paula, Pesini, Cecilia, Gálvez, Eva M., Ramírez-Labrada, Ariel, Arias, Maykel, Sanz-Pamplona, Rebeca, and Pardo, Julián more...
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KILLER cells ,COLORECTAL cancer ,CELL analysis ,CANCER patients ,CANCER treatment - Abstract
Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC. Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity. Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA
+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control. Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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12. All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity.
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Ramírez-Labrada, Ariel, Pesini, Cecilia, Santiago, Llipsy, Hidalgo, Sandra, Calvo-Pérez, Adanays, Oñate, Carmen, Andrés-Tovar, Alejandro, Garzón-Tituaña, Marcela, Uranga-Murillo, Iratxe, Arias, Maykel A., Galvez, Eva M., and Pardo, Julián more...
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CELL-mediated cytotoxicity ,KILLER cells ,CELL death ,CELL physiology ,IMMUNOLOGIC memory ,PSYCHONEUROIMMUNOLOGY - Abstract
NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might affect not only tumour cell elimination by NK cells but, in addition, the generation of T cell responses against the tumour that would contribute to efficient tumour elimination and generate cancer immune memory preventing potential recurrences. [ABSTRACT FROM AUTHOR] more...
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- 2022
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13. Integrated analysis of circulating immune cellular and soluble mediators reveals specific COVID19 signatures at hospital admission with utility for prediction of clinical outcomes.
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Uranga-Murillo, Iratxe, Morte, Elena, Hidalgo, Sandra, Pesini, Cecilia, García-Mulero, Sandra, Sierra, Jose L., Santiago, Llipsy, Arias, Maykel, De Miguel, Diego, del Mar Encabo-Berzosa, María, Gracia-Tello, Borja, Sanz-Pamplona, Rebeca, Martinez-Lostao, Luis, Galvez, Eva M., Paño-Pardo, Jose R., Ramirez-Labrada, Ariel, and Pardo, Julian more...
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- 2022
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14. Biological relevance of Granzymes A and K during E. coli sepsis.
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Uranga-Murillo, Iratxe, Tapia, Elena, Garzón-Tituaña, Marcela, Ramirez-Labrada, Ariel, Santiago, Llipsy, Pesini, Cecilia, Esteban, Patricia, Roig, Francisco J., Galvez, Eva M., Bird, Phillip I., Pardo, Julián, and Arias, Maykel more...
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- 2021
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15. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis.
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Garzón-Tituaña, Marcela, Sierra-Monzón, José L., Comas, Laura, Santiago, Llipsy, Khaliulina-Ushakova, Tatiana, Uranga-Murillo, Iratxe, Ramirez-Labrada, Ariel, Tapia, Elena, Morte-Romea, Elena, Algarate, Sonia, Couty, Ludovic, Camerer, Eric, Bird, Phillip I., Seral, Cristina, Luque, Pilar, Paño-Pardo, José R., Galvez, Eva M., Pardo, Julián, and Arias, Maykel more...
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- 2021
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16. Determination of the Concentration of IgG against the Spike Receptor-Binding Domain That Predicts the Viral Neutralizing Activity of Convalescent Plasma and Serum against SARS-CoV-2.
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Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, del Mar Encabo-Berzosa, Maria, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, and Fernández, Antonio more...
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CONVALESCENT plasma , *COVID-19 , *SARS-CoV-2 , *COVID-19 treatment , *IMMUNOGLOBULIN G - Abstract
Simple Summary: Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Nevertheless, its efficacy in patients with COVID-19 remains uncertain. Thus, the establishment and validation of standardized methods that predict the viral neutralizing (VN) activity of plasma against SARS-CoV-2 is of utmost importance to appraise its therapeutic value. Using an in-house quantitative ELISA test and two independent cohorts with a total of 345 donors, we found that plasma and serum from most convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, with varying concentrations which correlate with previous disease severity and gender. Anti-RBD IgG plasma concentration significantly correlated with the plasma/serum VN activity against SARS-CoV-2 in vitro. Several hundred millions of people have been diagnosed of coronavirus disease 2019 (COVID-19), causing millions of deaths and a high socioeconomic burden. SARS-CoV-2, the causative agent of COVID-19, induces both specific T- and B-cell responses, being antibodies against the virus detected a few days after infection. Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Using an in-house quantitative ELISA test, we found that plasma from 177 convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, although at very different concentrations which correlated with previous disease severity and gender. Anti-RBD IgG plasma concentrations significantly correlated with the plasma viral neutralizing activity (VN) against SARS-CoV-2 in vitro. Similar results were found using an independent cohort of serum from 168 convalescent health workers. These results validate an in-house RBD IgG ELISA test in a large cohort of COVID-19 convalescent patients and indicate that plasma from all convalescent donors does not contain a high enough amount of anti-SARS-CoV-2-RBD neutralizing IgG to prevent SARS-CoV-2 infection in vitro. The use of quantitative anti-RBD IgG detection systems might help to predict the efficacy of the passive immunization using plasma from patients recovered from SARS-CoV-2. [ABSTRACT FROM AUTHOR] more...
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- 2021
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17. Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.
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Lagunas, Kristel Martinez, Savcigil, Deniz Pinar, Zrilic, Matea, Fraile, Carlos Carvajal, Craxton, Andrew, Self, Emily, Uranga-Murillo, Iratxe, de Miguel, Diego, Arias, Maykel, Willenborg, Sebastian, Piekarek, Michael, Albert, Marie Christine, Nugraha, Kalvin, Lisewski, Ina, Janakova, Erika, Igual, Natalia, Tonnus, Wulf, Hildebrandt, Ximena, Ibrahim, Mohammed, and Ballegeer, Marlies more...
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CELL death , *VIRUS diseases , *SKIN regeneration , *DEATH receptors , *SOFT tissue injuries , *INTERFERON gamma , *BONE marrow cells - Abstract
The article focuses on a study conducted to analyze the physiological role of cellular FLICE-like inhibitory protein (cFLIP) cleavage by Caspase-8 in preventing cell death in a variety of pathological circumstances. It found that a cleavage-resistant cFLIP mutant, CflipD377A, showed greater vulnerability to the SARS-CoV, slowed skin wound healing, and increased Sharpin deficiency-induced tissue damage. more...
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- 2023
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18. Biological relevance of Granzymes A and K during E. coli sepsis
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Ariel Ramirez-Labrada, Phillip I. Bird, Llipsy Santiago, Elena Tapia, Julián Pardo, Marcela Garzón-Tituaña, Maykel Arias, Iratxe Uranga-Murillo, Francisco J Roig, Patricia Perez Esteban, Eva M. Galvez, Cecilia Pesini, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Gobierno de Aragón, Asociación Española Contra el Cáncer, ARAID Foundation, Agencia Estatal de Investigación (España), Uranga Murillo, Iratxe, Tapia, Elena, Garzón, Marcela, Ramírez-Labrada, Ariel, Santiago, Llipsy, Pesini, Cecilia, Esteban, Patricia, Roig, Francisco J., Gálvez Buerba, Eva Mª, Bird, Phillip I., Pardo, Julián, Arias, Maykel, Uranga Murillo, Iratxe [0000-0001-8411-984X], Tapia, Elena [0000-0002-4275-1406], Garzón, Marcela [0000-0001-6778-0636], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Santiago, Llipsy [0000-0002-1861-5981], Pesini, Cecilia [0000-0002-8707-2722], Esteban, Patricia [0000-0003-4123-3524], Roig, Francisco J. [0000-0002-8853-2428], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Bird, Phillip I. [0000-0002-6695-606X], Pardo, Julián [0000-0003-0154-0730], and Arias, Maykel [0000-0002-9730-2210] more...
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Inflammation ,Proteases ,Granzyme A ,Medicine (miscellaneous) ,Bacterial sepsis ,Biology ,medicine.disease ,Microbiology ,Proinflammatory cytokine ,Sepsis ,Granzyme ,medicine ,biology.protein ,Tumor necrosis factor alpha ,Granzyme K ,medicine.symptom ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Abstract
6 figures.-- Supplemenatry material available.--This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions., [Aims]: Recent in vitro findings suggest that the serine protease Granzyme K (GzmK) may act as a proinflammatory mediator. However, its role in sepsis is unknown. Here we aim to understand the role of GzmK in a mouse model of bacterial sepsis and compare it to the biological relevance of Granzyme A (GzmA)., [Methods]: Sepsis was induced in WT, GzmA-/- and GzmK-/- mice by an intraperitoneal injection of 2x108 CFU from E. coli. Mouse survival was monitored during 5 days. Levels of IL-1α, IL-1β, TNFα and IL-6 in plasma were measured and bacterial load in blood, liver and spleen was analyzed. Finally, profile of cellular expression of GzmA and GzmK was analyzed by FACS., [Results]: GzmA and GzmK are not involved in the control of bacterial infection. However, GzmA and GzmK deficient mice showed a lower sepsis score in comparison with WT mice, although only GzmA deficient mice exhibited increased survival. GzmA deficient mice also showed reduced expression of some proinflammatory cytokines like IL1-α, IL-β and IL-6. A similar result was found when extracellular GzmA was therapeutically inhibited in WT mice using serpinb6b, which improved survival and reduced IL-6 expression. Mechanistically, active extracellular GzmA induces the production of IL-6 in macrophages by a mechanism dependent on TLR4 and MyD88., [Conclusions]: These results suggest that although both proteases contribute to the clinical signs of E. coli-induced sepsis, inhibition of GzmA is sufficient to reduce inflammation and improve survival irrespectively of the presence of other inflammatory granzymes, like GzmK., This work was supported by grant SAF2017-83120-C2-1-R and PID2020-113963RBI00 from the Ministry of Science, Innovation and Universities and FEDER (Group B29_17R, Aragon Government). IU-M , MG-T and CP were supported by a PhD fellowships from Aragon Government, Ministry of Science, Innovation and Universities (FPI) and Asociacion Española contra el Cancer (AECC). MA and LS were supported by a post-doctoral fellowship “Juan de la Cierva-formación” (MA, LS) and "Juan de la Cierva-incorporacion" (MA) from the Ministry of Science, Innovation and Universities. JP was supported by ARAID Foundation. more...
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- 2021
19. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis
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Julián Pardo, Pilar Luque, Ludovic Couty, Jose Luis Sierra-Monzón, Maykel Arias, Tatiana Khaliulina-Ushakova, José Ramón Paño-Pardo, Eric Camerer, Ariel Ramirez-Labrada, Cristina Seral, Phillip I. Bird, Laura Comas, Iratxe Uranga-Murillo, Marcela Garzón-Tituaña, Sonia Algarate, Elena Tapia, Llipsy Santiago, Eva M. Galvez, Elena Morte-Romea, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Gobierno de Aragón, ARAID Foundation, Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Santiago, Llipsy, Khaliulina, Tatiana, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Tapia, Elena, Morte Romea, Elena, Algarate, Sonia, Camerer, Eric, Bird, Phillip I., Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Pardo, Julián, Arias, Maykel, Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Santiago, Llipsy [0000-0002-1861-5981], Khaliulina, Tatiana [0000-0002-7930-2129], Uranga Murillo, Iratxe [0000-0001-8411-984X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Tapia, Elena [0000-0002-4275-1406], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-663], Camerer, Eric [0000-0002-6271-7125], Bird, Phillip I. [0000-0002-6695-606X], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], and Arias, Maykel [0000-0002-9730-2210] more...
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0301 basic medicine ,Male ,Medicine (miscellaneous) ,Granzymes ,Pathogenesis ,Mice ,0302 clinical medicine ,Molecular Targeted Therapy ,Precision Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Aged, 80 and over ,Mice, Knockout ,cecal ligation and puncture ,Granzyme A ,Middle Aged ,Killer Cells, Natural ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cytokines ,Tumor necrosis factor alpha ,Female ,medicine.symptom ,Inflammation Mediators ,Research Paper ,Peritonitis ,Spleen ,Inflammation ,Proinflammatory cytokine ,Sepsis ,03 medical and health sciences ,medicine ,Extracellular ,Animals ,Humans ,Serpins ,Aged ,business.industry ,Interleukin-6 ,Macrophages ,Cecal ligation and puncture ,medicine.disease ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Disease Models, Animal ,030104 developmental biology ,Immunology ,business - Abstract
7 figures, 1 table., [Aims]: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis., [Methods]: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times., [Results]: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα., [Conclusions]: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology., This work was supported by grant SAF2017-83120-C2-1-R and SAF2014-54763-C2-2-R from the Ministry of Science, Innovation and Universities and FEDER (Group B29_17R, Aragon Government). MG and LS were supported by a PhD fellowship (FPI) from the Ministry of Science, Innovation and Universities. IUM was supported by a PhD fellowship from Aragon Government, MA was supported by a post-doctoral fellowship “Juan de la Cierva-formación” from the Ministry of Science, Innovation and Universities. JP was supported by ARAID Foundation. more...
- Published
- 2021
20. Cell death induced by cytotoxic CD8+ T cells is immunogenic and primes caspase-3-dependent spread immunity against endogenous tumor antigens
- Author
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David Sancho, Paula Jaime-Sánchez, Nacho Aguilo, Sofía C. Khouili, Julián Pardo, Iratxe Uranga-Murillo, Maykel Arias, Asociación de Padres de Niños Oncológicos de Aragón, Gobierno de Aragón (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Ministerio de Ciencia y Universidades (España), ARAID Foundation, Instituto de Salud Carlos III, Fundación ProCNIC, European Research Council, Universidad de Zaragoza, Jaime Sánchez, Paula, Uranga Murillo, Iratxe, Aguiló, Nacho, Chayeb Khouili, Sofia, Arias, Maykel, Sancho, David, Pardo, Julián, Jaime Sánchez, Paula [0000-0002-8731-4269, Uranga Murillo, Iratxe [0000-0001-8411-984X], Aguiló, Nacho [0000-0001-7897-9173], Chayeb Khouili, Sofia [0000-0002-7333-789X], Arias, Maykel [0000-0002-9730-2210], Sancho, David [0000-0003-2890-3984], and Pardo, Julián [0000-0003-0154-0730] more...
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Cytotoxic CD8+ T cells ,T-Lymphocytes ,Cytotoxicity ,Immunology ,chemical and pharmacologic phenomena ,Dendritic cells ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Antigen ,Immunologic ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Antigens ,RC254-282 ,Pharmacology ,Chemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,Immunogenicity ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Caspases ,Cancer cell ,Cancer research ,Tumor immunology ,Molecular Medicine ,Immunogenic cell death ,Vaccine ,CD8 - Abstract
6 Figures, [Background] Elimination of cancer cells by some stimuli like chemotherapy and radiotherapy activates anticancer immunity after the generation of damage‐associated molecular patterns, a process recently named immunogenic cell death (ICD). Despite the recent advances in cancer immunotherapy, very little is known about the immunological consequences of cell death activated by cytotoxic CD8+ T (Tc) cells on cancer cells, that is, if Tc cells induce ICD on cancer cells and the molecular mechanisms involved., [Methods] ICD induced by Tc cells on EL4 cells was analyzed in tumor by vaccinating mice with EL4 cells killed in vitro or in vivo by Ag-specific Tc cells. EL4 cells and mutants thereof overexpressing Bcl-XL or a dominant negative mutant of caspase-3 and wild-type mice, as well as mice depleted of Tc cells and mice deficient in perforin, TLR4 and BATF3 were used. Ex vivo cytotoxicity of spleen cells from immunized mice was analyzed by flow cytometry. Expression of ICD signals (calreticulin, HMGB1 and interleukin (IL)-1β) was analyzed by flow cytometry and ELISA., [Results] Mice immunized with EL4.gp33 cells killed in vitro or in vivo by gp33-specific Tc cells were protected from parental EL4 tumor development. This result was confirmed in vivo by using ovalbumin (OVA) as another surrogate antigen. Perforin and TLR4 and BATF3-dependent type 1 conventional dendritic cells (cDC1s) were required for protection against tumor development, indicating cross-priming of Tc cells against endogenous EL4 tumor antigens. Tc cells induced ICD signals in EL4 cells. Notably, ICD of EL4 cells was dependent on caspase-3 activity, with reduced antitumor immunity generated by caspase-3–deficient EL4 cells. In contrast, overexpression of Bcl-XL in EL4 cells had no effect on induction of Tc cell antitumor response and protection., [Conclusions] Elimination of tumor cells by Ag-specific Tc cells is immunogenic and protects against tumor development by generating new Tc cells against EL4 endogenous antigens. This finding helps to explain the enhanced efficacy of T cell-dependent immunotherapy and provide a molecular basis to explain the epitope spread phenomenon observed during vaccination and chimeric antigen receptor (CAR)-T cell therapy. In addition, they suggest that caspase-3 activity in the tumor may be used as a biomarker to predict cancer recurrence during T cell-dependent immunotherapies., The authors would like to acknowledge the use of Servicios Científico Técnicos del CIBA (IACS-Universidad de Zaragoza) and Servicios Apoyo Investigación de la Universidad de Zaragoza. more...
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- 2020
21. Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.
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Martinez Lagunas K, Savcigil DP, Zrilic M, Carvajal Fraile C, Craxton A, Self E, Uranga-Murillo I, de Miguel D, Arias M, Willenborg S, Piekarek M, Albert MC, Nugraha K, Lisewski I, Janakova E, Igual N, Tonnus W, Hildebrandt X, Ibrahim M, Ballegeer M, Saelens X, Kueh A, Meier P, Linkermann A, Pardo J, Eming S, Walczak H, MacFarlane M, Peltzer N, and Annibaldi A more...
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- Animals, Mice, Caspase 8 genetics, Skin metabolism, Tumor Necrosis Factor-alpha metabolism, Apoptosis, Virus Diseases
- Abstract
Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, Cflip
D377A , exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)-induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs. more...- Published
- 2023
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22. Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants.
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Conde E, Vercher E, Soria-Castellano M, Suarez-Olmos J, Mancheño U, Elizalde E, Rodriguez ML, Glez-Vaz J, Casares N, Rodríguez-García E, Hommel M, González-Aseguinolaza G, Uranga-Murillo I, Pardo J, Alkorta G, Melero I, Lasarte J, and Hervas-Stubbs S more...
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- Animals, Humans, Male, Mice, Epitopes genetics, Immunotherapy methods, Immunotherapy, Adoptive methods, Neoplasms genetics, Tumor Escape genetics
- Abstract
Background: Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2'3'-cyclic GMP-AMP (2'3'-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism., Methods: Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2'3'-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed., Results: Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy. In this setting, the CART/STING-L combination, but not the monotherapy with CART cells or STING-L, restrained tumor progression and enhanced overall survival, showing abscopal effects on distal STING-L-non-treated tumors. Interestingly, a secondary immune response against non-chimeric antigen receptor-targeted Ags (epitope spreading), as determined by major histocompatibility complex-I-tetramer staining, was fostered and its intensity correlated with the efficacy of the combination. This was consistent with the oligoclonal expansion of host T cells, as revealed by in-depth T-cell receptor repertoire analysis. Moreover, only in the combination group did the activation of endogenous T cells translate into a systemic antitumor response. Importantly, the epitope spreading and the antitumor effects of the combination were fully dependent on host STING signaling and Batf3-dependent DCs, and were partially dependent on Perf release by CART cells. Interestingly, the efficacy of the CART/STING-L treatment also depended on STING signaling in CART cells., Conclusions: Our data show that 2'3'-cGAMP is a suitable adjuvant to combine with CART-cell therapy, allowing the induction of an endogenous T-cell response that prevents the outgrowth of Ag-loss tumor variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.) more...
- Published
- 2021
- Full Text
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23. Cell death induced by cytotoxic CD8 + T cells is immunogenic and primes caspase-3-dependent spread immunity against endogenous tumor antigens.
- Author
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Jaime-Sanchez P, Uranga-Murillo I, Aguilo N, Khouili SC, Arias MA, Sancho D, and Pardo J
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Cell Death, Dendritic Cells metabolism, Lymphoma, T-Cell metabolism, Mice, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic metabolism, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Caspase 3 metabolism, Dendritic Cells immunology, Lymphoma, T-Cell immunology, Lymphoma, T-Cell pathology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Background: Elimination of cancer cells by some stimuli like chemotherapy and radiotherapy activates anticancer immunity after the generation of damage-associated molecular patterns, a process recently named immunogenic cell death (ICD). Despite the recent advances in cancer immunotherapy, very little is known about the immunological consequences of cell death activated by cytotoxic CD8
+ T (Tc) cells on cancer cells, that is, if Tc cells induce ICD on cancer cells and the molecular mechanisms involved., Methods: ICD induced by Tc cells on EL4 cells was analyzed in tumor by vaccinating mice with EL4 cells killed in vitro or in vivo by Ag-specific Tc cells. EL4 cells and mutants thereof overexpressing Bcl-XL or a dominant negative mutant of caspase-3 and wild-type mice, as well as mice depleted of Tc cells and mice deficient in perforin, TLR4 and BATF3 were used. Ex vivo cytotoxicity of spleen cells from immunized mice was analyzed by flow cytometry. Expression of ICD signals (calreticulin, HMGB1 and interleukin (IL)-1β) was analyzed by flow cytometry and ELISA., Results: Mice immunized with EL4.gp33 cells killed in vitro or in vivo by gp33-specific Tc cells were protected from parental EL4 tumor development. This result was confirmed in vivo by using ovalbumin (OVA) as another surrogate antigen. Perforin and TLR4 and BATF3-dependent type 1 conventional dendritic cells (cDC1s) were required for protection against tumor development, indicating cross-priming of Tc cells against endogenous EL4 tumor antigens. Tc cells induced ICD signals in EL4 cells. Notably, ICD of EL4 cells was dependent on caspase-3 activity, with reduced antitumor immunity generated by caspase-3-deficient EL4 cells. In contrast, overexpression of Bcl-XL in EL4 cells had no effect on induction of Tc cell antitumor response and protection., Conclusions: Elimination of tumor cells by Ag-specific Tc cells is immunogenic and protects against tumor development by generating new Tc cells against EL4 endogenous antigens. This finding helps to explain the enhanced efficacy of T cell-dependent immunotherapy and provide a molecular basis to explain the epitope spread phenomenon observed during vaccination and chimeric antigen receptor (CAR)-T cell therapy. In addition, they suggest that caspase-3 activity in the tumor may be used as a biomarker to predict cancer recurrence during T cell-dependent immunotherapies., Competing Interests: Competing interests: JP reports research funding from BMS and Gilead and speaker honoraria from Gilead and Pfizer., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2020
- Full Text
- View/download PDF
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