{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T13:49:01Z","timestamp":1784123341263,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["A48"],"award-info":[{"award-number":["A48"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["A90"],"award-info":[{"award-number":["A90"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Agency (JST)","doi-asserted-by":"publisher","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}],"id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["A48"],"award-info":[{"award-number":["A48"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["A90"],"award-info":[{"award-number":["A90"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT)","doi-asserted-by":"publisher","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["A48"],"award-info":[{"award-number":["A48"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["A90"],"award-info":[{"award-number":["A90"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["A48"],"award-info":[{"award-number":["A48"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["A90"],"award-info":[{"award-number":["A90"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED Basis for Supporting Innovative Drug Discovery and Life Science Research","doi-asserted-by":"publisher","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}]},{"name":"Thailand Research Fund under the Royal Golden Jubilee Ph.D. Program","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}]},{"name":"Thailand Science Research and Innovation Fundamental Fund and the National Research Council of Thailand under the Research Team Promotion grant","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}]},{"name":"Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["JP223fa627004"],"award-info":[{"award-number":["JP223fa627004"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["23ama121032j0002"],"award-info":[{"award-number":["23ama121032j0002"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["PHD\/0096\/2560"],"award-info":[{"award-number":["PHD\/0096\/2560"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["2I01 BX000972-05"],"award-info":[{"award-number":["2I01 BX000972-05"]}]},{"name":"Mike Slive Foundation for Prostate Cancer Researc","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is a rare disease characterized by malignant cells derived from the epithelial cells of the biliary duct system. Despite extensive treatments, the prognosis for CCA remains poor, emphasizing the critical need for the development of novel treatments. Considerable attention has been directed towards innate immune effector cells, which can recognize tumor cells independently of the major histocompatibility complex, laying the foundation for the development of off-the-shelf drugs. In this study, we cultured innate immune cells obtained from the peripheral blood of healthy adults and conducted a comparative analysis of the effector functions against CCA cell lines by V\u03b42 \u03b3\u03b4 T cells and NK cells. This analysis was performed using standard short- and long-term cytotoxicity assays, as well as ELISA for IFN-\u03b3. V\u03b42 \u03b3\u03b4 T cells demonstrated cytotoxicity and IFN-\u03b3 production in response to CCA cells in a TCR-dependent manner, particularly in the presence of tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate, a bisphosphonate prodrug. In contrast, direct killing and antibody-dependent cellular cytotoxicity were relatively slow and weak. Conversely, NK cells displayed potent, direct cytotoxicity against CCA cells. In summary, both V\u03b42 \u03b3\u03b4 T cells and NK cells show promise as innate immune effector cells for adoptive transfer therapy in the context of CCA.<\/jats:p>","DOI":"10.3390\/cells13161322","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T12:13:14Z","timestamp":1723119194000},"page":"1322","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Analysis of the Effector Functions of V\u03b42 \u03b3\u03b4 T Cells and NK Cells against Cholangiocarcinoma Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7213-9085","authenticated-orcid":false,"given":"Inthuon","family":"Kulma","sequence":"first","affiliation":[{"name":"Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan"},{"name":"Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani 12121, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kesara","family":"Na-Bangchang","sequence":"additional","affiliation":[{"name":"Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani 12121, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Carvallo Herrera","sequence":"additional","affiliation":[{"name":"Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifeanyi Theodora","family":"Ndubuisi","sequence":"additional","affiliation":[{"name":"Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2748-9418","authenticated-orcid":false,"given":"Hiromi","family":"Tomono","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8496-8294","authenticated-orcid":false,"given":"Craig T.","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Iowa, Iowa City, IA 52246, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruki","family":"Okamura","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Mukae","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5024-0614","authenticated-orcid":false,"given":"Yoshimasa","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan"},{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"398","DOI":"10.3892\/ijo.2015.3019","article-title":"Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness","volume":"47","author":"Wattanawongdon","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.3748\/wjg.v11.i18.2748","article-title":"Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines","volume":"11","author":"Tepsiri","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)","volume":"13","author":"Banales","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","first-page":"475","article-title":"Cancer incidence in Thailand, 1988\u20131991","volume":"4","author":"Vatanasapt","year":"1995","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/liv.14095","article-title":"Cholangiocarcinoma: Epidemiology and risk factors","volume":"1","author":"Khan","year":"2019","journal-title":"Liver Int."},{"key":"ref_6","first-page":"605","article-title":"Risk factors for cholangiocarcinoma in Thailand: A systematic review and meta-analysis","volume":"19","author":"Luvira","year":"2018","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/MOG.0b013e3282fbf9b3","article-title":"Cholangiocarcinoma: Lessons from Thailand","volume":"24","author":"Sripa","year":"2008","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/j.1365-3024.1986.tb00861.x","article-title":"Opisthorchis viverrini: Pathogenesis of infection in immunodeprived hamsters","volume":"8","author":"Flavell","year":"1986","journal-title":"Parasite Immunol."},{"key":"ref_9","first-page":"213","article-title":"Immune responsiveness and parasite-specific antibody levels in human hepatobiliary disease associated with Opisthorchis viverrini infection","volume":"84","author":"Sithithaworn","year":"1991","journal-title":"Clin. Exp. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s005340050094","article-title":"Resection of intrahepatic cholangiocarcinoma: A Western experience","volume":"6","author":"Valverde","year":"1999","journal-title":"J. Hepatobiliary Pancreat. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11894-017-0542-4","article-title":"Update on the diagnosis and treatment of cholangiocarcinoma","volume":"19","author":"Doherty","year":"2017","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1155\/2013\/196412","article-title":"Serum markers of intrahepatic cholangiocarcinoma","volume":"34","author":"Malaguarnera","year":"2013","journal-title":"Dis. Markers"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/j.1365-2036.2011.04851.x","article-title":"Review article: Surgical, neo-adjuvant and adjuvant management strategies in biliary tract cancer","volume":"34","author":"Skipworth","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e17832","DOI":"10.1097\/MD.0000000000017832","article-title":"Significant response to anti-PD-1 based immunotherapy plus lenvatinib for recurrent intrahepatic cholangiocarcinoma with bone metastasis: A case report and literature review","volume":"98","author":"Chen","year":"2019","journal-title":"Medicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1084\/jem.20030584","article-title":"\u03b3\u03b4 T cells provide an early source of interferon gamma in tumor immunity","volume":"198","author":"Gao","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0014-5793(01)03191-X","article-title":"Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli","volume":"509","author":"Hintz","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1084\/jem.20021500","article-title":"Human T cell receptor \u03b3\u03b4 cells recognize endogenous mevalonate metabolites in tumor cells","volume":"197","author":"Gober","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/cmi.2012.46","article-title":"Multifunctional immune responses of HMBPP-specific V\u03b32V\u03b42 T cells in M. tuberculosis and other infections","volume":"10","author":"Chen","year":"2013","journal-title":"Cell. Mol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1182\/blood-2012-05-430470","article-title":"Key implication of CD277\/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human \u03b3\u03b4 T-cell subset","volume":"120","author":"Harly","year":"2012","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.immuni.2014.03.003","article-title":"The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human V\u03b39V\u03b42 T cells","volume":"40","author":"Sandstrom","year":"2014","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.2174\/138161210793563617","article-title":"Molecular targets of the nitrogen containing bisphosphonates: The molecular pharmacology of prenyl synthase inhibition","volume":"16","author":"Dunford","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eaay5516","DOI":"10.1126\/science.aay5516","article-title":"Butyrophilin 2A1 is essential for phosphoantigen reactivity by \u03b3\u03b4 T cells","volume":"367","author":"Rigau","year":"2020","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Levy, E.M., Roberti, M.P., and Mordoh, J. (2011). Natural killer cells in human cancer: From biological functions to clinical applications. J. Biomed. Biotechnol., 2011.","DOI":"10.1155\/2011\/676198"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.immuni.2017.10.008","article-title":"The broad spectrum of human natural killer cell diversity","volume":"47","author":"Freud","year":"2017","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fattori, S., Gorvel, L., Granjeaud, S., Rochigneux, P., Rouvi\u00e8re, M.S., Ben Amara, A., Boucherit, N., Paul, M., Dauplat, M.M., and Thomassin-Piana, J. (2021). Quantification of immune variables from liquid biopsy in breast cancer patients links V\u03b42. Cancers, 13.","DOI":"10.3390\/cancers13030441"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109871","DOI":"10.1016\/j.celrep.2021.109871","article-title":"NKG2A expression identifies a subset of human V\u03b42 T cells exerting the highest antitumor effector functions","volume":"37","author":"Cazzetta","year":"2021","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/eji.201040959","article-title":"Expression and function of PD-1 in human \u03b3\u03b4 T cells that recognize phosphoantigens","volume":"41","author":"Iwasaki","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e1450","DOI":"10.1002\/cti2.1450","article-title":"Circulating CXCR5+ natural killer cells are expanded in patients with myasthenia gravis","volume":"12","author":"Ge","year":"2023","journal-title":"Clin. Transl. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kaulfuss, M., Mietz, J., Fabri, A., Vom Berg, J., M\u00fcnz, C., and Chijioke, O. (2023). The NK cell checkpoint NKG2A maintains expansion capacity of human NK cells. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-37779-6"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Mariotti, F.R., Ingegnere, T., Landolina, N., Vacca, P., Munari, E., and Moretta, L. (2023). Analysis of the mechanisms regulating soluble PD-1 production and function in human NK cells. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1229341"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41392-023-01653-8","article-title":"\u03b3\u03b4 T cells: Origin and fate, subsets, diseases and immunotherapy","volume":"8","author":"Hu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sivori, S., Della Chiesa, M., Carlomagno, S., Quatrini, L., Munari, E., Vacca, P., Tumino, N., Mariotti, F.R., Mingari, M.C., and Pende, D. (2020). Inhibitory receptors and checkpoints in human NK cells, Implications for the immunotherapy of cancer. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.02156"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"331","DOI":"10.7150\/ijbs.22809","article-title":"Effect of IL-18 on the expansion and phenotype of human natural killer cells: Application to cancer immunotherapy","volume":"14","author":"Senju","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/S0168-8278(85)80002-7","article-title":"Biliary adenocarcinoma. Characterisation of three new human tumor cell lines","volume":"1","author":"Knuth","year":"1985","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Du, J., Lv, X., Zhang, Z., Huang, Z., and Zhang, E. (2023). Revisiting targeted therapy and immunotherapy for advanced cholangiocarcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1142690"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1002\/ijc.20445","article-title":"Potential of human \u03b3\u03b4 T lymphocytes for immunotherapy of cancer","volume":"112","author":"Kabelitz","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1146\/annurev.immunol.18.1.975","article-title":"\u03b3\u03b4 cells: A right time and a right place for a conserved third way of protection","volume":"18","author":"Hayday","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e007955","DOI":"10.1136\/jitc-2023-007955","article-title":"Therapeutic avenues for \u03b3\u03b4 T cells in cancer","volume":"11","author":"Costa","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40425-019-0501-8","article-title":"Allogenic V\u03b39V\u03b42 T cell as new potential immunotherapy drug for solid tumor: A case study for cholangiocarcinoma","volume":"7","author":"Alnaggar","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41423-020-0515-7","article-title":"Allogeneic V\u03b39V\u03b42 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer","volume":"18","author":"Xu","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Nakashima, M., Tanaka, Y., Okamura, H., Kato, T., Imaizumi, Y., Nagai, K., Miyazaki, Y., and Murota, H. (2024). Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia-Lymphoma. Cells, 13.","DOI":"10.3390\/cells13020128"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Umeyama, Y., Taniguchi, H., Gyotoku, H., Senju, H., Tomono, H., Takemoto, S., Yamaguchi, H., Tagod, M.S.O., Iwasaki, M., and Tanaka, Y. (2023). Three distinct mechanisms underlying human \u03b3\u03b4 T cell-mediated cytotoxicity against malignant pleural mesothelioma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1058838"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5133","DOI":"10.4049\/jimmunol.153.11.5133","article-title":"Recognition and destruction of virus-infected cells by human gamma delta CTL","volume":"153","author":"Bukowski","year":"1994","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Howard, J., Zaidi, I., Loizon, S., Mercereau-Puijalon, O., D\u00e9chanet-Merville, J., and Mamani-Matsuda, M. (2018). Human V\u03b39V\u03b42 T Lymphocytes in the Immune Response to. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02760"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/infdis\/jiv600","article-title":"Frequent Malaria Drives Progressive V\u03b42 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood","volume":"213","author":"Farrington","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1128\/iai.62.3.855-862.1994","article-title":"Polyclonal expansion of peripheral \u03b3\u03b4 T cells in human Plasmodium falciparum malaria","volume":"62","author":"Ho","year":"1994","journal-title":"Infect. Immun."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Jagannathan, P., Lutwama, F., Boyle, M.J., Nankya, F., Farrington, L.A., McIntyre, T.I., Bowen, K., Naluwu, K., Nalubega, M., and Musinguzi, K. (2017). V\u03b42+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-10624-3"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/imr.12927","article-title":"Fast-acting \u03b3\u03b4 T-cell subpopulation and protective immunity against infections","volume":"298","author":"Shen","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Rasi, V., Wood, D.C., Eickhoff, C.S., Xia, M., Pozzi, N., Edwards, R.L., Walch, M., Bovenschen, N., and Hoft, D.F. (2021). Granzyme A Produced by \u03b39\u03b42 T Cells Activates ER Stress Responses and ATP Production, and Protects Against Intracellular Mycobacterial Replication Independent of Enzymatic Activity. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.712678"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1093\/infdis\/165.3.506","article-title":"\u03b3\u03b4 T lymphocytes in human tuberculosis","volume":"165","author":"Barnes","year":"1992","journal-title":"J. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1086\/323600","article-title":"Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by V\u03b39\/V\u03b42 T lymphocytes","volume":"184","author":"Dieli","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/ijc.28372","article-title":"Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma","volume":"134","author":"Cui","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Hwang, S., Han, J., Baek, J.S., Tak, E., Song, G.W., Lee, S.G., Jung, D.H., Park, G.C., Ahn, C.S., and Kim, N. (2019). Cytotoxicity of human hepatic intrasinusoidal CD56bright natural killer cells against hepatocellular carcinoma cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071564"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"63","DOI":"10.21873\/anticanres.16135","article-title":"Cytotoxicity of human hepatic intrasinusoidal \u03b3\u03b4 T cells depends on phospho-antigen and NK receptor signaling","volume":"43","author":"Kang","year":"2023","journal-title":"Anticancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/cas.13491","article-title":"Expansion of human \u03b3\u03b4 T cells for adoptive immunotherapy using a bisphosphonate prodrug","volume":"109","author":"Tanaka","year":"2018","journal-title":"Cancer Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/16\/1322\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:32:04Z","timestamp":1760110324000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/16\/1322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,8]]},"references-count":56,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cells13161322"],"URL":"https:\/\/doi.org\/10.3390\/cells13161322","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,8]]}}}