{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T19:01:22Z","timestamp":1770318082898,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"crossref","award":["PICT2019\/255"],"award-info":[{"award-number":["PICT2019\/255"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Instituto Nacional del C\u00e1ncer, Fundaci\u00f3n Florencio Fiorini"},{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Glioblastoma (GBM) is the most aggressive and common primary brain tumor, with a median survival of less than a year after diagnosis. \u03b3\u03b4 T lymphocytes are immune cells that can migrate to tumors and induce malignant cells\u2019 apoptosis. Our previous in silico studies showed that higher \u03b3\u03b4 T-cell infiltration in GBM correlates with better patient survival, and in vitro experiments showed that GMB supernatants promote an antitumoral profile in \u03b3\u03b4 T cells. Extracellular vesicles (EVs) play a critical role in cell communication, particularly in tumor microenvironment modulation. Here, we studied the mechanisms responsible for \u03b3\u03b4 T lymphocyte activation by GBM-derived EVs, together with the effect of these EVs on \u03b3\u03b4 T cells from GBM patients. For that, \u03b3\u03b4 T cells were purified from peripheral blood, and EVs were obtained from U251 cell supernatants by differential centrifugation. After EV characterization, we evaluated the \u03b3\u03b4 T cell\u2013EV interaction and \u03b3\u03b4 T-cell modulation by EVs. Results showed that EVs induced an increase in CD69 expression, cytotoxicity, and TNF-\u03b1 and IFN-\u03b3 production in \u03b3\u03b4 T cells in a MIC-dependent mechanism. These results provide valuable insights for developing targeted immunotherapies in GBM patients.<\/jats:p>","DOI":"10.3390\/biology15030275","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:11Z","timestamp":1770122771000},"page":"275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Small Messengers: Glioblastoma-Derived Extracellular Vesicles Modulate \u03b3\u03b4 T Lymphocytes Through a MIC-Dependent Mechanism"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4176-3976","authenticated-orcid":false,"given":"Micaela","family":"Rosato","sequence":"first","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"},{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3580-9901","authenticated-orcid":false,"given":"Paula","family":"Saibene V\u00e9lez","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5865-0346","authenticated-orcid":false,"given":"Alejandra","family":"Infante Cruz","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4769-6570","authenticated-orcid":false,"given":"Mat\u00edas A.","family":"Pibuel","sequence":"additional","affiliation":[{"name":"Instituto de Estudios de la Inmunidad Humoral (IDEHU)\u2013CONICET, Departamento de Microbiolog\u00eda, Inmunolog\u00eda y Biotecnolog\u00eda, Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Fuentes","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4984-6555","authenticated-orcid":false,"given":"M\u00f3nica","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"},{"name":"Departamento de Microbiolog\u00eda, Parasitolog\u00eda e Inmunolog\u00eda, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3244-8512","authenticated-orcid":false,"given":"Juan","family":"Iturrizaga","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n Neurocirug\u00eda, Instituto de Investigaciones M\u00e9dicas A. Lanari, Universidad de Buenos Aires, Buenos Aires 1427, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7568-6026","authenticated-orcid":false,"given":"Pablo E.","family":"Espil","sequence":"additional","affiliation":[{"name":"Servicio de Neurocirug\u00eda, Cl\u00ednica y Maternidad Santa Isabel, Buenos Aires 1406, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1801-469X","authenticated-orcid":false,"given":"Silvia","family":"Berner","sequence":"additional","affiliation":[{"name":"Servicio de Neurocirug\u00eda, Cl\u00ednica y Maternidad Santa Isabel, Buenos Aires 1406, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0438-1942","authenticated-orcid":false,"given":"Gabriela V.","family":"Salamone","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"},{"name":"Departamento de Microbiolog\u00eda, Parasitolog\u00eda e Inmunolog\u00eda, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9222-9571","authenticated-orcid":false,"given":"Carolina C.","family":"Jancic","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Experimental\u2013CONICET\u2013Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina"},{"name":"Departamento de Microbiolog\u00eda, Parasitolog\u00eda e Inmunolog\u00eda, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO classification of tumors of the central nervous system: A summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Liang, J., Li, T., Zhao, J., Wang, C., and Sun, H. (2022). Current understanding of the human microbiome in glioma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.781741"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rafii, S., Ghouzlani, A., Naji, O., Ssi, S.A., Kandoussi, S., Lakhdar, A., and Badou, A. (2023). A2AR as a prognostic marker and a potential immunotherapy target in human glioma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076688"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noaa200","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013\u20132017","volume":"22","author":"Ostrom","year":"2020","journal-title":"Neuro-Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s12032-025-02830-1","article-title":"Unlocking glioblastoma: Breakthroughs in molecular mechanisms and next-generation therapies","volume":"42","author":"Fariah","year":"2025","journal-title":"Med. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/1040-8428(94)00169-3","article-title":"Concepts in multistage carcinogenesis","volume":"21","author":"Ito","year":"1995","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Boulhen, C., Ssi, S.A., Benthami, H., Razzouki, I., Lakhdar, A., Karkouri, M., and Badou, A. (2023). TMIGD2 as a potential therapeutic target in glioma patients. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1173518"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"21504","DOI":"10.1038\/s41598-021-00835-0","article-title":"The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis","volume":"11","author":"Ghouzlani","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Vieira de Castro, J., Gon\u00e7alves, C.S., Hormigo, A., and Costa, B.M. (2020). Exploiting the complexities of glioblastoma stem cells: Insights for cancer initiation and therapeutic targeting. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155278"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Weenink, B., French, P.J., Sillevis Smitt, P.A.E.L., Debets, R., and Geurts, M. (2020). Immunotherapy in glioblastoma: Current shortcomings and future perspectives. Cancers, 2.","DOI":"10.3390\/cancers12030751"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41577-022-00763-8","article-title":"The roles of extracellular vesicles in the immune system","volume":"23","author":"Buzas","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27066","DOI":"10.3402\/jev.v4.27066","article-title":"Biological properties of extracellular vesicles and their physiological functions","volume":"4","author":"Siljander","year":"2015","journal-title":"J. Extracell. Vesicle"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/ncb1800","article-title":"Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers","volume":"10","author":"Skog","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41556-018-0250-9","article-title":"Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication","volume":"21","author":"Mathieu","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e12190","DOI":"10.1002\/jev2.12190","article-title":"In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part II: Pathology","volume":"11","author":"Yates","year":"2022","journal-title":"J. Extracell. Vesicle"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tankov, S., and Walker, P.R. (2021). Glioma-derived extracellular vesicles\u2014Far more than local mediators. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.679954"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/ki.2010.278","article-title":"Exosomes\/microvesicles as a mechanism of cell-to-cell communication","volume":"78","author":"Camussi","year":"2010","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41590-021-00899-0","article-title":"Extracellular vesicles in immunomodulation and tumor progression","volume":"22","author":"Marar","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.4049\/jimmunol.0900970","article-title":"Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes","volume":"183","author":"Wieckowski","year":"2009","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1053\/j.gastro.2005.03.045","article-title":"Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: Role in immune escape","volume":"128","author":"Huber","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Whiteside, T.L. (2021). The role of tumor-derived exosomes (TEX) in shaping anti-tumor immune competence. Cells, 10.","DOI":"10.3390\/cells10113054"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Qi, Z., Long, X., Liu, J., and Cheng, P. (2022). Glioblastoma microenvironment and its reprogramming by oncolytic virotherapy. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.819363"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ghazi, B., Harmak, Z., Rghioui, M., Kone, A.-S., El Ghanmi, A., and Badou, A. (2024). Decoding the secret of extracellular vesicles in the immune tumor microenvironment of the glioblastoma: On the border of kingdoms. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1423232"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lv, J., Liu, Z., Ren, X., Song, S., Zhang, Y., and Wang, Y. (2025). \u03b3\u03b4T cells, a key subset of T cell for cancer immunotherapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1562188"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/322145a0","article-title":"Identification of a putative second T-cell receptor","volume":"322","author":"Brenner","year":"1986","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, C.Q., Lim, P.Y., and Tan, A.H.-M. (2024). Gamma\/delta T cells as cellular vehicles for anti-tumor immunity. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1282758"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Subhi-Issa, N., Manzano, D.T., Pereiro Rodr\u00edguez, A., Sanchez Ramon, S., Perez Segura, P., and Oca\u00f1a, A. (2025). \u03b3\u03b4 T Cells: Game changers in immune cell therapy for cancer. Cancers, 17.","DOI":"10.3390\/cancers17071063"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/nri3904","article-title":"\u03b3\u03b4 T cells in cancer","volume":"15","author":"Serre","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1093\/intimm\/dxm031","article-title":"Preferential recognition of a microbial metabolite by human V\u03b32V\u03b42 T cells","volume":"19","author":"Puan","year":"2007","journal-title":"Int. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e22892","DOI":"10.4161\/onci.22892","article-title":"Tumor cell recognition by \u03b3\u03b4 T lymphocytes: T-cell receptor vs. NK-cell receptors","volume":"2","author":"Correia","year":"2013","journal-title":"OncoImmunology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1093276","DOI":"10.1080\/2162402X.2015.1093276","article-title":"NKG2D- and T-cell receptor-dependent lysis of malignant glioma cell lines by human \u03b3\u03b4 T cells: Modulation by temozolomide and A disintegrin and metalloproteases 10 and 17 inhibitors","volume":"5","author":"Chitadze","year":"2016","journal-title":"OncoImmunology"},{"key":"ref_32","first-page":"8996","article-title":"MICA\/NKG2D-mediated immunogene therapy of experimental gliomas","volume":"63","author":"Friese","year":"2003","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1126\/science.1978758","article-title":"Recognition by human V\u03b39\/V\u03b42 T cells of a GroEL homolog on Daudi Burkitt\u2019s lymphoma cells","volume":"250","author":"Fisch","year":"1990","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/imm.12835","article-title":"Modulation of \u03b3\u03b4 T-cell activation by neutrophil elastase","volume":"153","author":"Towstyka","year":"2018","journal-title":"Immunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/eji.201343664","article-title":"Neutrophils suppress \u03b3\u03b4 T-cell function","volume":"44","author":"Sabbione","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s11060-021-03787-7","article-title":"Glioblastoma cells potentiate the induction of the Th1-like profile in phosphoantigen-stimulated \u03b3\u03b4 T lymphocytes","volume":"153","author":"Rosso","year":"2021","journal-title":"J. Neurooncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1093\/neuonc\/noy187","article-title":"Characterization of single microvesicles in plasma from glioblastoma patients","volume":"21","author":"Fraser","year":"2019","journal-title":"Neuro-Oncol."},{"key":"ref_38","first-page":"3","article-title":"Isolation and characterization of exosomes from cell culture supernatants and biological fluids","volume":"30","author":"Amigorena","year":"2006","journal-title":"Curr. Protoc. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e12299","DOI":"10.1002\/jev2.12299","article-title":"A Compendium of single extracellular vesicle flow cytometry","volume":"12","author":"Welsh","year":"2023","journal-title":"J. Extracell. Vesicles"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"W534","DOI":"10.1093\/nar\/gkaf388","article-title":"TIMER3: An enhanced resource for tumor immune analysis","volume":"53","author":"Cui","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1038\/s41467-017-01196-x","article-title":"Coding and noncoding landscape of extracellular RNA released by human glioma stem cells","volume":"8","author":"Wei","year":"2017","journal-title":"Nat. Commun."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/3\/275\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T05:17:39Z","timestamp":1770268659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/3\/275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,3]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["biology15030275"],"URL":"https:\/\/doi.org\/10.3390\/biology15030275","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,3]]}}}