{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T14:57:07Z","timestamp":1778770627020,"version":"3.51.4"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ama221331"],"award-info":[{"award-number":["JP24ama221331"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24bm1123051"],"award-info":[{"award-number":["JP24bm1123051"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22zf0127009"],"award-info":[{"award-number":["JP22zf0127009"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Science and Technology Agency FOREST","award":["JPMJFR2060"],"award-info":[{"award-number":["JPMJFR2060"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["23K27470"],"award-info":[{"award-number":["23K27470"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["24K22072"],"award-info":[{"award-number":["24K22072"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["23K06710"],"award-info":[{"award-number":["23K06710"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["24K18588"],"award-info":[{"award-number":["24K18588"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Takara Bio, Inc"},{"name":"Aichi Cancer Center Joint Research Project on Priority Areas"},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive immunotherapy potentially applicable to many types of solid tumors. Although gynecologic malignancies are promising targets for TIL therapy, its objective efficacy has not been established. Current TIL culture typically involves incubation of dissociated samples with high-dose IL-2 (HD-IL2) for weeks to enrich tumor-reactive T cells. While this protocol has been successfully used for melanoma TIL, it has not necessarily been optimized for other cancers. Here we investigated the method of efficiently expanding TILs derived from patients with gynecological cancers. TILs were incubated with HD-IL2 (HD-IL2-TILs) or stimulated with K562 cells expressing anti-CD3 mAb and CD80 (\u03b1CD3\/CD80-TILs). We found that the \u03b1CD3\/CD80-TILs showed significantly better proliferation than HD-IL2-TILs. The TIL populations that predominantly expanded upon \u03b1CD3\/CD80 stimulation expressed high levels of PD-1 and CD28. CD28 co-stimulation was essential to overcome PD-1\u2013mediated signals for growth suppression. We also identified DUSP4 as a negative regulator of TIL proliferation by downregulating ERK phosphorylation. The \u03b1CD3\/CD80-TILs were reactive to tumor cells as shown by IFN-\u03b3 secretion and CD107a expression. Moreover, the \u03b1CD3\/CD80-TILs were efficiently transduced with a chimeric cytokine receptor that we had previously developed to provide constitutive IL-7 signaling, resulting in superior in vivo persistence and antitumor effects without exogenous cytokine support in mouse models. Collectively, this study shows that direct stimulation of TILs with anti-CD3 mAb and CD28 co-stimulation achieves efficient expansion of tumor-reactive TILs. Genetic engineering of cytokine signaling in TILs may further enhance TIL functions and replace cytokine administration after TIL infusion.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf259","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T15:07:08Z","timestamp":1758899228000},"page":"3618-3633","source":"Crossref","is-referenced-by-count":2,"title":["Efficient expansion of tumor-infiltrating lymphocytes from gynecologic cancer"],"prefix":"10.1093","volume":"214","author":[{"given":"Tetsuya","family":"Matsukawa","sequence":"first","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]},{"name":"Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Nagoya,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsunenori","family":"Ouchida","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taeko","family":"Hayakawa","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitomi","family":"Kasuya","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chisato","family":"Umehara","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuyuki","family":"Chiyoda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wataru","family":"Yamagami","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9716-7194","authenticated-orcid":false,"given":"Waki","family":"Hosoda","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Diagnostics, Aichi Cancer Center , Nagoya,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0834-9285","authenticated-orcid":false,"given":"Shiro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Aichi Cancer Center , Nagoya,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6216-6730","authenticated-orcid":false,"given":"Yuki","family":"Kagoya","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"2025122315374364900_vkaf259-B1","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1200\/JCO.22.01365","article-title":"Idecabtagene vicleucel for relapsed\/refractory multiple myeloma: real-world experience from the Myeloma CAR T Consortium","volume":"41","author":"Hansen","year":"2023","journal-title":"J Clin Oncol"},{"key":"2025122315374364900_vkaf259-B2","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1038\/s41591-022-01969-y","article-title":"A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma","volume":"28","author":"Bachy","year":"2022","journal-title":"Nat Med"},{"key":"2025122315374364900_vkaf259-B3","doi-asserted-by":"crossref","first-page":"5233","DOI":"10.1200\/JCO.2008.16.5449","article-title":"Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens","volume":"26","author":"Dudley","year":"2008","journal-title":"J Clin Oncol"},{"key":"2025122315374364900_vkaf259-B4","doi-asserted-by":"crossref","first-page":"4550","DOI":"10.1158\/1078-0432.CCR-11-0116","article-title":"Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy","volume":"17","author":"Rosenberg","year":"2011","journal-title":"Clin Cancer Res"},{"key":"2025122315374364900_vkaf259-B5","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1093\/annonc\/mdz398","article-title":"Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis","volume":"30","author":"Dafni","year":"2019","journal-title":"Ann 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in type I and II endometrial cancer","volume":"114","author":"de Jong","year":"2009","journal-title":"Gynecol Oncol"},{"key":"2025122315374364900_vkaf259-B18","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1200\/JCO.2014.58.9093","article-title":"Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells","volume":"33","author":"Stevanovi\u0107","year":"2015","journal-title":"J Clin Oncol"},{"key":"2025122315374364900_vkaf259-B19","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1097\/00002371-199410000-00004","article-title":"Intraperitoneal adoptive immunotherapy of ovarian carcinoma with tumor-infiltrating lymphocytes and low-dose recombinant interleukin-2: a pilot trial","volume":"16","author":"Freedman","year":"1994","journal-title":"J Immunother Emphasis Tumor Immunol"},{"key":"2025122315374364900_vkaf259-B20","first-page":"1934","article-title":"Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer","volume":"51","author":"Aoki","year":"1991","journal-title":"Cancer Res"},{"key":"2025122315374364900_vkaf259-B21","doi-asserted-by":"crossref","first-page":"e006822","DOI":"10.1136\/jitc-2023-006822","article-title":"Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma","volume":"12","author":"Amaria","year":"2024","journal-title":"J Immunother Cancer."},{"key":"2025122315374364900_vkaf259-B22","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1097\/CJI.0b013e318209c94c","article-title":"Establishment and large-scale expansion of minimally cultured \u201cyoung\u201d tumor infiltrating lymphocytes for adoptive transfer therapy","volume":"34","author":"Itzhaki","year":"2011","journal-title":"J Immunother"},{"key":"2025122315374364900_vkaf259-B23","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1097\/CJI.0b013e31818403d5","article-title":"Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy","volume":"31","author":"Tran","year":"2008","journal-title":"J Immunother"},{"key":"2025122315374364900_vkaf259-B24","doi-asserted-by":"crossref","first-page":"113229","DOI":"10.1016\/j.jim.2022.113229","article-title":"TIL expansion with high dose IL-2 or low dose IL-2 with anti-CD3\/anti-CD28 stimulation provides different quality of TIL-expanded T cell clones","volume":"503","author":"Kongkaew","year":"2022","journal-title":"J Immunol Methods"},{"key":"2025122315374364900_vkaf259-B25","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1007\/s00262-018-2211-3","article-title":"Ex vivo expanded tumour-infiltrating lymphocytes from ovarian cancer patients release anti-tumour cytokines in response to autologous 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