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1. Extracellular vesicles derived from antigen-presenting cells pulsed with foot and mouth virus vaccine-antigens act as carriers of viral proteins and stimulate B cell response

Author

Florencia Menay, Federico Cocozza, Maria J. Gravisaco, Analia Elisei, Javier Ignacio Re, Alejandra Ferella, Claudia Waldner, and Claudia Mongini

Subjects
extracellular vesicles, foot and mouth disease virus, antiviral immune response, antigen presenting cells, B cell activation, Immunologic diseases. Allergy, RC581-607
Abstract

Foot and mouth disease (FMD) is a highly contagious infection caused by FMD-virus (FMDV) that affects livestock worldwide with significant economic impact. The main strategy for the control is vaccination with FMDV chemically inactivated with binary ethylenimine (FMDVi). In FMDV infection and vaccination, B cell response plays a major role by providing neutralizing/protective antibodies in animal models and natural hosts. Extracellular vesicles (EVs) and small EVs (sEVs) such as exosomes are important in cellular communication. EVs secreted by antigen-presenting cells (APC) like dendritic cells (DCs) participate in the activation of B and T cells through the presentation of native antigen membrane-associated to B cells or by transferring MHC-peptide complexes to T cells and even complete antigens from DCs. In this study, we demonstrate for the first time that APC activated with the FMDVi O1 Campos vaccine-antigens secrete EVs expressing viral proteins/peptides that could stimulate FMDV-specific immune response. The secretion of EVs-FMDVi is a time-dependent process and can only be isolated within the first 24 h post-activation. These vesicles express classical EVs markers (CD9, CD81, and CD63), along with immunoregulatory molecules (MHC-II and CD86). With an average size of 155 nm, they belong to the category of EVs. Studies conducted in vitro have demonstrated that EVs-FMDVi express antigens that can stimulate a specific B cell response against FMDV, including both marginal zone B cells (MZB) and follicular B cells (FoB). These vesicles can also indirectly or directly affect T cells, indicating that they express both B and T epitopes. Additionally, lymphocyte expansion induced by EVs-FMDVi is greater in splenocytes that have previously encountered viral antigens in vivo. The present study sheds light on the role of EVs derived from APC in regulating the adaptive immunity against FMDV. This novel insight contributes to our current understanding of the immune mechanisms triggered by APC during the antiviral immune response. Furthermore, these findings may have practical implications for the development of new vaccine platforms, providing a rational basis for the design of more effective vaccines against FMDV and other viral diseases.

Published
2024
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2. Differential proteomics argues against a general role for CD9, CD81 or CD63 in the sorting of proteins into extracellular vesicles

Author

Yé Fan, Cédric Pionneau, Federico Cocozza, Pierre‐Yves Boëlle, Solenne Chardonnet, Stéphanie Charrin, Clotilde Théry, Pascale Zimmermann, and Eric Rubinstein

Subjects
CD63, CD81, CD9, exosomes, extracellular vesicles, IgSF8, Cytology, QH573-671
Abstract

Abstract The tetraspanins CD9, CD81 and CD63 are major components of extracellular vesicles (EVs). Yet, their impact on EV composition remains under‐investigated. In the MCF7 breast cancer cell line CD63 was as expected predominantly intracellular. In contrast CD9 and CD81 strongly colocalized at the plasma membrane, albeit with different ratios at different sites, which may explain a higher enrichment of CD81 in EVs. Absence of these tetraspanins had little impact on the EV protein composition as analysed by quantitative mass spectrometry. We also analysed the effect of concomitant knock‐out of CD9 and CD81 because these two tetraspanins play similar roles in several cellular processes and associate directly with two Ig domain proteins, CD9P‐1/EWI‐F/PTGFRN and EWI‐2/IGSF8. These were the sole proteins significantly decreased in the EVs of double CD9‐ and CD81‐deficient cells. In the case of EWI‐2, this is primarily a consequence of a decreased cell expression level. In conclusion, this study shows that CD9, CD81 and CD63, commonly used as EV protein markers, play a marginal role in determining the protein composition of EVs released by MCF7 cells and highlights a regulation of the expression level and/or trafficking of CD9P‐1 and EWI‐2 by CD9 and CD81.

Published
2023
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3. Extracellular vesicles and co-isolated endogenous retroviruses differently affect dendritic cells

Author

Federico Cocozza, Lorena Martin-Jaular, Lien Lippens, Aurelie Di Cicco, Yago A Arribas, Florent Dingli, Michael Richard, Louise Merle, Patrick Poullet, Damarys Loew, Daniel Lévy, An Hendrix, George Kassiotis, Alain Joliot, Mercedes Tkach, and Clotilde Théry

Abstract

Cells secrete membrane-enclosed extracellular vesicles (EVs) and non-vesicular nanoparticles (ENPs) that may play a role in intercellular communication. Tumor-derived EVs have been proposed either to induce immune priming of antigen presenting cells, or, to be immuno-suppressive agents promoting tumor immune escape. We suspect that such disparate functions are due to variable composition in EV subtypes and ENPs of the analyzed EV preparations. We aimed to exhaustively characterize the array of secreted EVs and ENPs of murine tumor cell lines. Unexpectedly, we identified virus-like particles (VLPs) from endogenous murine leukemia virus in preparations of EVs produced by tumor cells. We established a robust protocol to separate small (s)EVs from VLPs and ENPs. We compared their protein composition and analyzed their functional interaction with target dendritic cells (DCs). ENPs were poorly captured and did not affect DCs. sEVs specifically induced DC death. A mixed EV/VLP preparation was the most efficient to induce DC maturation and antigen presentation. Our results call for systematic re-evaluation of the respective proportions and functions of non-viral EVs and VLPs produced by tumors and their contribution to anti-tumor immune responses and to tumor progression.

Published
2023

4. Extracellular vesicles from triple negative breast cancer promote pro-inflammatory macrophages associated with better clinical outcome

Author

Mercedes Tkach, Jessie Thalmensi, Eleonora Timperi, Paul Gueguen, Nathalie Névo, Eleonora Grisard, Philemon Sirven, Federico Cocozza, Alizée Gouronnec, Lorena Martin-Jaular, Mabel Jouve, Fabien Delisle, Nicolas Manel, Derek C. Rookhuizen, Coralie L. Guerin, Vassili Soumelis, Emanuela Romano, Elodie Segura, and Clotilde Théry

Subjects
Extracellular Vesicles, Multidisciplinary, Macrophages, Humans, Triple Negative Breast Neoplasms
Abstract

Tumor associated macrophages (TAMs), which differentiate from circulating monocytes, are pervasive across human cancers and comprise heterogeneous populations. The contribution of tumor-derived signals to TAM heterogeneity is not well understood. In particular, tumors release both soluble factors and extracellular vesicles (EVs), whose respective impact on TAM precursors may be different. Here, we show that triple negative breast cancer cells (TNBCs) release EVs and soluble molecules promoting monocyte differentiation toward distinct macrophage fates. EVs specifically promoted proinflammatory macrophages bearing an interferon response signature. The combination in TNBC EVs of surface CSF-1 promoting survival and cargoes promoting cGAS/STING or other activation pathways led to differentiation of this particular macrophage subset. Notably, macrophages expressing the EV-induced signature were found among patients’ TAMs. Furthermore, higher expression of this signature was associated with T cell infiltration and extended patient survival. Together, this data indicates that TNBC-released CSF-1-bearing EVs promote a tumor immune microenvironment associated with a better prognosis in TNBC patients.

Published
2022

5. Extracellular vesicles containing ACE2 efficiently prevent infection by SARS‐CoV‐2 Spike protein‐containing virus

Author

Nicolas Manel, Clotilde Théry, Olivier Schwartz, Federico Cocozza, Nathalie Névo, Mercedes Tkach, Julian Buchrieser, Xavier Lahaye, Lorena Martin-Jaular, Ester Piovesana, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Université Paris sciences et lettres (PSL), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), This work was supported by Institut Curie, INSERM, CNRS, grants H2020-MSCA-ITN (722148, TRAIN-EV), INCa (11548) and Fondation ARC (PGA1 RF20180206962) to C Théry, LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043) to C. Théry and N. Manel, LABEX VRI (ANR-10-LABX-77), ANRS (France Recherche Nord & Sud Sida-HIV Hépatites, ECTZ36691, ECTZ71745), Sidaction (17-1-AAE-11097-2), ANR (ANR-19-CE15-0018-01, ANR-18-CE92-0022-01), DIM1HEALTH to N Manel. N Manel thanks Mutuelle Bleue for support., ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2011), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-19-CE15-0018,NUCLEONDRIA,Fonctions émergentes du détection de l'immunité innée cGAS dans les organites à ADN(2019), ANR-18-CE92-0022,cGAS-Vac,Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants(2018), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), LAHAYE, Xavier, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Biologie des cellules dendritiques - - DCBIOL2011 - ANR-11-LABX-0043 - LABX - VALID, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Fonctions émergentes du détection de l'immunité innée cGAS dans les organites à ADN - - NUCLEONDRIA2019 - ANR-19-CE15-0018 - AAPG2019 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants - - cGAS-Vac2018 - ANR-18-CE92-0022 - AAPG2018 - VALID, and Virus et Immunité - Virus and immunity (CNRS-UMR3569)

Subjects
0301 basic medicine, Histology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Short Communication, viruses, Priming (immunology), ACE2, urologic and male genital diseases, TMPRSS2, Virus, SARS‐CoV‐2, Cell Line, 03 medical and health sciences, Extracellular Vesicles, 0302 clinical medicine, Humans, Receptor, skin and connective tissue diseases, Infectivity, Innate immune system, biology, Chemistry, SARS-CoV-2, Lentivirus, Serine Endopeptidases, Lipid bilayer fusion, COVID-19, Cell Biology, Virus Internalization, biology.organism_classification, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Spike Glycoprotein, Coronavirus, Receptors, Virus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Angiotensin-Converting Enzyme 2, EV therapy, Caco-2 Cells, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; SARS-CoV-2 entry is mediated by binding of the spike protein (S) to the surface receptor ACE2 and subsequent priming by host TMPRSS2 allowing membrane fusion. Here, we produced extracellular vesicles (EVs) exposing ACE2 and demonstrate that ACE2-EVs are efficient decoys for SARS-CoV-2 S protein-containing lentivirus. Reduction of infectivity positively correlates with the level of ACE2, is much more efficient than with soluble ACE2 and further enhanced by the inclusion of TMPRSS2.

Published
2020

6. Extracellular vesicles containing ACE2 efficiently prevent infection by SARS-CoV-2 Spike protein-containing virus

Author

Lorena Martin-Jaular, Mercedes Tkach, Nicolas Manel, Federico Cocozza, Nathalie Névo, Julian Buchrieser, Ester Piovesana, Clotilde Théry, Olivier Schwartz, Xavier Lahaye, Immunité et cancer (U932), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Infectivity, 0303 health sciences, biology, Chemistry, [SDV]Life Sciences [q-bio], Spike Protein, Lipid bilayer fusion, Priming (immunology), biology.organism_classification, TMPRSS2, Virus, Cell biology, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Lentivirus, Receptor, hormones, hormone substitutes, and hormone antagonists, 030304 developmental biology
Abstract

16 SARS-CoV-2 entry is mediated by binding of the spike protein (S) to the surface 17 receptor ACE2 and subsequent priming by TMPRRS2 allowing membrane fusion. 18 Here, we produced extracellular vesicles (EVs) exposing ACE2 and demonstrate that 19 ACE2-EVs are efficient decoys for SARS-CoV-2 S protein-containing lentivirus. 20 Reduction of infectivity positively correlates with the level of ACE2, is 500 to 1500 21 times more efficient than with soluble ACE2 and further enhanced by the inclusion of 22 TMPRSS2. 23 24 MAIN 25 SARS-CoV-2 is the causative agent of COVID-19 infection outbreak 1. Viral entry into 26 host cells is mediated by the interaction of the spike (S) protein on the surface of 27 (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint this version posted July 8, 2020. ; https://doi.

Published
2020

7. Systemic administration of imiquimod as an adjuvant improves immunogenicity of a tumor-lysate vaccine inducing the rejection of a highly aggressive T-cell lymphoma

Author

Federico Cocozza, Florencia Menay, María José Gravisaco, Paula Di Sciullo, Claudia Mongini, and C. Waldner

Subjects
0301 basic medicine, Cell Extracts, Cellular immunity, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.medical_treatment, Immunology, Inmunología, Imiquimod, Lymphoma, T-Cell, Cancer Vaccines, 03 medical and health sciences, Mice, 0302 clinical medicine, Adjuvants, Immunologic, Antigens, Neoplasm, Cell Line, Tumor, TLR, CD40, Immunology and Allergy, Medicine, T-cell lymphoma, Animals, Humans, Mice, Inbred BALB C, business.industry, Immunogenicity, Graft vs Tumor Effect, purl.org/becyt/ford/3.1 [https], TLR7, Immunotherapy, medicine.disease, Disease Models, Animal, Medicina Básica, 030104 developmental biology, Toll-Like Receptor 7, T-CELL LYMPHOMA-VACCINE, Cancer research, Systemic administration, IMIQUIMOD, purl.org/becyt/ford/3 [https], Female, business, Adjuvant, 030215 immunology, medicine.drug
Abstract

T-cell lymphomas include diverse malignancies. They are rare, some have low survival rates and they lack curative therapies. The aim of this work was to assess whether employing the TLR7 agonist imiquimod and the T-cell costimulatory molecule CD40 or the combination of both as adjuvants of a cell lysate vaccine could enhance the antitumor immune response using a murine T-cell lymphoma model. Immunization with LBC-lysate and imiquimod protected almost all vaccinated animals. A specific humoral and a Th1-type cellular immunity were induced in mice that rejected the lymphoma, characterized by an elevated number of CD4 + T-cells and secretion of IFN-γ, locally and systemically. In contrast, CD40 alone or in combination with imiquimod did not improve the protective response obtained with LBC-lysate and imiquimod. Systemic administration of imiquimod proved to have high potential to serve as a vaccine adjuvant for the treatment of T-cell lymphomas and was effective in this immunotherapy model. Fil: Di Sciullo, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Menay, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Cocozza, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Gravisaco, María José. Instituto Nacional de Tecnología Agropecuaria; Argentina Fil: Waldner, Claudia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Mongini, Claudia. Instituto Nacional de Tecnología Agropecuaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina

Published
2019

8. Cyclophosphamide enhances the release of tumor exosomes that elicit a specific immune response in vivo in a murine T-cell lymphoma

Author

Federico Cocozza, Pura Isabel Sampedro, Rodrigo Farid Tsacalian, Claudia Mongini, C. Waldner, Ivana Soria, Florencia Menay, María José Gravisaco, and Analia Elisei

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, 030231 tropical medicine, Inmunología, Exosomes, Lymphoma, T-Cell, Exosome, Cancer Vaccines, T-CELL LYMPHOMA, 03 medical and health sciences, Extracellular Vesicles, Mice, TUMOR-VACCINE, 0302 clinical medicine, Immune system, Antigen, Cell Line, Tumor, Cytotoxic T cell, Animals, 030212 general & internal medicine, Cyclophosphamide, EXOSOMES, General Veterinary, General Immunology and Microbiology, Chemistry, Immunogenicity, Public Health, Environmental and Occupational Health, Immunity, EXTRACELLULAR VESICLES, Acquired immune system, Cytotoxicity Tests, Immunologic, Xenograft Model Antitumor Assays, Microvesicles, Disease Models, Animal, Medicina Básica, Infectious Diseases, Cancer research, Molecular Medicine, Female, CD8
Abstract

Exosomes are 60–150 nm small extracellular vesicles (EVs) released by most cells. Tumor-cell-derived exosomes, used as a vaccine, elicit a specific cytotoxic response against tumor cells, usually with a greater immunogenicity than tumor-cell lysates. However, the number of exosomes isolated from culture cells is limited. In recent studies, it was observed that cells respond to different stressor stimuli such as cytotoxic drugs, hypoxia, acidosis, or radiation by increasing the release of EVs. In this study, using the murine LBC T-cell lymphoma, we found that cyclophosphamide significantly increased EVs yield. These EVs express exosome marker proteins such as TSG-101, CD9, CD81, and CD63. Furthermore, similar humoral and cellular immune responses were induced in vivo by EVs isolated from LBC-tumor cells whether they were grown under normal culture conditions (EVs C) or in the presence of cyclophosphamide (EVs CTX). Mice vaccinated either with EVs C or EVs CTX were similarly protected against an intraperitoneal challenge with LBC tumor cells. CD4+ and CD8+ IFN-γ secreting cells were induced in immunized mice and a specific cytotoxic cellular immune response was elicited in vitro. These results demonstrate that a Th1 response was induced by immunization with the EVs. Our findings suggest that treatment of tumor cells with cyclophosphamide is a useful method to enhance the secretion of EVs in sensitive cell lines without altering their antitumor properties and thus may be used to produce antigens for future design of cancer vaccines. Fil: Cocozza, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Menay, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Tsacalian, Rodrigo Farid. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Elisei, Analia. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina Fil: Sampedro, Pura Isabel. Universidad de Morón; Argentina Fil: Soria, Ivana. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina Fil: Waldner, Claudia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Gravisaco, María José. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina Fil: Mongini, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina. Universidad de Morón; Argentina

Published
2019

9. Exosomes Isolated from Ascites of T-Cell Lymphoma-Bearing Mice Expressing Surface CD24 and HSP-90 Induce a Tumor-Specific Immune Response

Author

Alejandrina Vendrell, María José Gravisaco, Claudia Mongini, Leticia Herschlik, Julieta De Toro, María Paula Di Sciullo, Rodrigo Tsacalian, Florencia Menay, C. Waldner, and Federico Cocozza

Subjects
0301 basic medicine, Lymphoma, medicine.medical_treatment, Immunology, exosomes, Biology, medicine.disease_cause, immune response, 03 medical and health sciences, ascites, Mice, 0302 clinical medicine, Immune system, Neoplasmas, Antigen, Cancer immunotherapy, Ascitis, Heat shock protein, medicine, Immunology and Allergy, Immune Response, T-lymphocytes, Original Research, Ratón, Microvesicles, Respuesta inmunológica, 030104 developmental biology, Linfoma, Cancer cell, Linfocitos-t, Cancer research, tumor vaccine, T-cell lymphoma, Carcinogenesis, CD8, 030215 immunology
Abstract

Extracellular vesicles (EVs), including endosome-derived nanovesicles (exosomes), are involved in cell–cell communication. Through transfer of their molecular contents, extracellular nanovesicles can alter the function of recipient cells. Due to these characteristics, EVs have shown potential as a new alternative for cancer immunotherapy. Tumor exosomes isolated from malignant ascites can activate dendritic cells, thereby priming the immune system to recognize and kill cancer cells. However, a suppressive role on tumor immune response has also been reported, suggesting that the neoplastic stage of carcinogenesis and the microenvironment where tumor cells grow may influence the amount of EVs released by the cell. This neoplastic stage and microenvironment may also impact EVs’ components such as proteins and miRNA, determining their biological behavior. Most T-cell lymphomas have an aggressive clinical course and poor prognosis. Consequently, complementary alternative therapies are needed to improve the survival rates achieved with conventional treatments. In this work, we have characterized EVs isolated from ascites of mice bearing a very aggressive murine T-cell lymphoma and have studied their immunogenic properties. Small EVs were isolated by differential centrifugation, ultrafiltration, and ultracentrifugation at 100,000 × g on a sucrose cushion. The EVs were defined as exosomes by their morphology and size analyzed by electron microscopy, their floating density on a sucrose gradient, as well as their expression of endosome marker proteins ALIX, TSG-101; the tetraspanins CD63, CD9, and CD81. In addition, they contain tumor antigens, the marker for malignancy CD24, the heat shock protein HSP-70, and an unusual surface expression of HSP-90 was demonstrated. The administration of EVs isolated from ascites (EVs A) into naïve-syngeneic mice induced both humoral and cellular immune responses that allowed the rejection of subsequent tumor challenges. However, the immunization had no effect on a non-related mammary adenocarcinoma, demonstrating that the immune response elicited was specific and also it induced immune memory. In vitro analysis demonstrated that T-cells from EVs A-immunized mice secrete IFN-γ in response to tumor stimulation. Furthermore, tumor-specific CD4+ and CD8+ IFN-γ secreting cells could be efficiently expanded from mice immunized with EVs A, showing that a T helper 1 response is involved in tumor rejection. Our findings confirm exosomes as promising defined acellular tumor antigens for the development of an antitumor vaccine. Inst. de Biotecnología Fil: Menay, Florencia. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina, Aires; Argentina Fil: Herschlik, Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina, Aires; Argentina Fil: Cocozza, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina, Aires; Argentina Fil: Tsacalian, Rodrigo Farid. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina, Aires; Argentina Fil: Gravisaco, Marí­a José. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina Fil: Di Sciullo, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina; Argentina Fil: Vendrell, Alejandrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina, Aires; Argentina Fil: Waldner, Claudia Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina, Aires; Argentina Fil: Mongini, Claudia. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos. Facultad de Medicina; Argentina

Published
2017

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