{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T18:22:34Z","timestamp":1778955754816,"version":"3.51.4"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Mesothelioma is an aggressive tumor in the pleural cavity that is difficult to treat. Diagnosis is usually late with minimal treatment options available for the patients and with unfavorable outcomes. However, recent advances in immunotherapy using \u03b3\u03b4 T cells may have potential against mesothelioma, given its ample tumoricidal and tumor-migratory properties could allow its infiltration to the widespread tumor mass. Thus, we hypothesize that V\u03b42 T cells can perform cytotoxic activities against mesothelioma especially when combined with immune checkpoint blocker against PD-1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human V\u03b42 T cells were expanded from peripheral blood mononuclear cells using Tetrakis\u2010pivaloyloxymethyl 2\u2010(thiazole\u20102\u2010ylamino) ethylidene\u20101,1\u2010bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of V\u03b42 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect V\u03b42 T cells post adoptive transfer and characteristics of pyroptosis in <jats:italic>ex vivo<\/jats:italic> mesothelioma tissue sections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Indeed, our data demonstrated that V\u03b42 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody <jats:italic>in vitro<\/jats:italic>, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of V\u03b42 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of V\u03b42 T cells into the tumor, especially to cells with BTN2A1 expression (a V\u03b42 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by V\u03b42 T cells. This was verified by V\u03b42 T\/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1\u03b2 and IL-18.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>V\u03b42 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing V\u03b42 T cells in promoting pyroptosis. Taken together, our work demonstrated that V\u03b42 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma. <\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1282710","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T11:43:53Z","timestamp":1700739833000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Anti-PD1 does not improve pyroptosis induced by \u03b3\u03b4 T cells but promotes tumor regression in a pleural mesothelioma mouse model"],"prefix":"10.3389","volume":"14","author":[{"given":"Ka Sin","family":"Lui","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuodong","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoi 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