{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:35:10Z","timestamp":1791282910895,"version":"4.1.0"},"reference-count":57,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"7","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Guangzhou Science and Technology Innovation development Special fund","award":["202102020386"],"award-info":[{"award-number":["202102020386"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103331"],"award-info":[{"award-number":["82103331"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171825"],"award-info":[{"award-number":["82171825"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82202036"],"award-info":[{"award-number":["82202036"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Existing treatments for cholangiocarcinoma have poor efficacy. However, chimeric antigen receptor\u2010T (CAR\u2010T) cells are emerging as a potential therapeutic strategy. Solid tumors possess multiple adverse factors in an immunosuppressive microenvironment that impair CAR\u2010T cell infiltration and function. This study aimed to improve the function of CAR\u2010T cells through knock down immune checkpoints and immunosuppressive molecular receptors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We evaluated the expression of epidermal growth factor receptor (EGFR) and B7 homolog 3 protein (B7H3) antigens in cholangiocarcinoma tissues using immunohistochemistry and screened specific immune checkpoints in the cholangiocarcinoma microenvironment via flow cytometry. Subsequently, we engineered CAR\u2010T cells targeting EGFR and B7H3 antigens. We simultaneously knocked down immune checkpoints and immunosuppressive molecular receptors in CAR\u2010T cells by constructing two clusters of small hairpin RNAs and evaluated the engineered CAR\u2010T cells for antitumor activity both in vitro, using tumor cell lines and cholangiocarcinoma organoid models, and in vivo, using humanized mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We observed high expression of EGFR and B7H3 antigens in cholangiocarcinoma tissues. EGFR\u2010CAR\u2010T and B7H3\u2010CAR\u2010T cells demonstrated specific anti\u2010tumor activity. We found an abundance of programmed cell death protein 1 (PD\u20101), T cell immunoglobulin and mucin domain\u2010containing protein 3 (Tim\u20103), and T cell immunoglobulin and ITIM domain (Tigit) on infiltrated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in the cholangiocarcinoma microenvironment. We then decreased the expression of these 3 proteins on the surface of CAR\u2010T cells, named PTG\u2010scFV\u2010CAR\u2010T cells. Furthermore, we knocked\u2010down the expression of transforming growth factor beta receptor (TGF\u03b2R), interleukin\u201010 receptor (IL\u201010R), and interleukin\u20106 receptor (IL\u20106R) of PTG\u2010scFV\u2010CAR\u2010T cells. Those cells, named PTG\u2010T16R\u2010scFV\u2010CAR\u2010T cells, potently killed tumor cells in vitro and promoted apoptosis of tumor cells in a cholangiocarcinoma organoid model. Finally, the PTG\u2010T16R\u2010scFv\u2010CAR\u2010T cells showed greater inhibitory effect on tumor growth in vivo, and were superior in prolonging the survival of mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our results revealed that PTG\u2010T16R\u2010scFV\u2010CAR\u2010T cells with knockdown of sextuplet inhibitory molecules exhibited strong immunity against cholangiocarcinoma and long\u2010term efficacy both in vitro and in vivo. This strategy provides an effective and personalized immune cell therapy against cholangiocarcinoma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12452","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T23:22:53Z","timestamp":1686180173000},"page":"788-807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Enhancement of CAR\u2010T cell activity against cholangiocarcinoma by simultaneous knockdown of six inhibitory membrane proteins"],"prefix":"10.34133","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3219-6426","authenticated-orcid":false,"given":"Yidan","family":"Qiao","sequence":"first","affiliation":[{"name":"the Third Affiliated Hospital of Sun Yat\u2010sen University","place":["Guangzhou, P. R. China"]},{"name":"Institute of Human Virology","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University","place":["Guangzhou, P. 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