{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:51:02Z","timestamp":1790484662336,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T00:00:00Z","timestamp":1580688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19110989"],"award-info":[{"award-number":["19110989"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Persistent exposure to tumor antigens results in exhausted tumor-infiltrating T cells (TILs) that express the immune checkpoint molecules, PD-1 and Tim3, and lack anti-tumor immunity. To examine the exhausted status of TILs in ovarian cancer, the potential for cytokine production, proliferation and cytotoxicity by purified PD-1+ Tim3+ CD8 TILs was assessed. The production of IFN-\u03b3 and TNF-\u03b1 by PD-1+ Tim3+ CD8 TILs remained the same in an intracellular cytokine staining assay and was higher in a cytokine catch assay than that by PD-1\u2212 Tim3\u2212 and PD-1+ Tim3\u2212 CD8 TILs. %Ki67+ was higher in PD-1+ Tim3+ CD8 TILs than in PD-1\u2212 Tim3\u2212 CD8 TILs. However, patients with high PD-1+ Tim3+ CD8 TILs had a poor prognosis. The potential for cytotoxicity was then examined. %Perforin+ and %granzyme B+ were lower in PD-1+ Tim3+ CD8 TILs than in PD-1\u2212 Tim3\u2212 and PD-1+ Tim3\u2212 CD8 TILs. To observe the potential for direct cytotoxicity by T cells, a target cell line expressing membrane-bound anti-CD3scFv was newly established and a cytotoxic assay targeting these cells was performed. The cytotoxicity of PD-1+ Tim3+ CD8 TILs was significantly lower than that of PD-1\u2212 Tim3\u2212 and PD-1+ Tim3\u2212 CD8 TILs. Even though PD-1+ Tim3+ CD8 TILs in ovarian cancer showed a sustained potential for cytokine production and proliferation, cytotoxicity was markedly impaired, which may contribute to the poor prognosis of patients with ovarian cancer. Among the impaired functions of exhausted TILs, cytotoxicity may be an essential target for cancer immunotherapy.<\/jats:p>","DOI":"10.1093\/intimm\/dxaa010","type":"journal-article","created":{"date-parts":[[2020,2,1]],"date-time":"2020-02-01T12:11:07Z","timestamp":1580559067000},"page":"397-405","source":"Crossref","is-referenced-by-count":38,"title":["PD-1+ Tim3+ tumor-infiltrating CD8 T cells sustain the potential for IFN-\u03b3 production, but lose cytotoxic activity in ovarian cancer"],"prefix":"10.1093","volume":"32","author":[{"given":"Masaaki","family":"Sawada","sequence":"first","affiliation":[{"name":"Department of Clinical Research in Tumor Immunology , Osaka, Japan"},{"name":"Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine , Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Clinical Research in Tumor Immunology , Osaka, 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