{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T18:05:39Z","timestamp":1783706739236,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["21cm0106406h0006"],"award-info":[{"award-number":["21cm0106406h0006"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"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":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2024,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The selection of highly specific target antigens is critical for the development of clinically efficient and safe chimeric antigen receptors (CARs). In search of diagnostic marker for malignant mesothelioma (MM), we have established SKM9\u20102 monoclonal antibody (mAb) which recognizes a MM\u2010specific molecule, sialylated Protein HEG homolog 1 (HEG1), with high specificity and sensitivity. In this study, to develop a novel therapeutic approach against MM, we generated SKM9\u20102 mAb\u2010derived CARs that included the CD28 (SKM\u201028z) or 4\u20101BB (SKM\u2010BBz) costimulatory domain. SKM\u201028z CAR\u2010T cells showed continuous growth and enhanced Tim\u20103, LAG\u20103, and PD\u20101 expression in vitro, which might be induced by tonic signaling caused by self\u2010activation; however, these phenotypes were not observed in SKM\u2010BBz CAR\u2010T cells. In addition, SKM\u2010BBz CAR\u2010T cells exhibited slightly stronger in vitro killing activity against MM cell lines than SKM\u201028z CAR\u2010T cells. More importantly, only SKM\u2010BBz CAR\u2010T cells, but not SKM\u201028z CAR\u2010T cells, significantly inhibited tumor growth in vivo in a MM cell line xenograft mouse model. Gene expression profiling and reporter assays revealed differential signaling pathway activation; in particular, SKM\u2010BBz CAR\u2010T cells exhibited enhanced NF\u2010kB signaling and reduced NFAT activation. In addition, SKM\u2010BBz CAR\u2010T cells showed upregulation of early memory markers, such as TCF7 and CCR7, as well as downregulation of pro\u2010apoptotic proteins, such as BAK1 and BID, which may be associated with phenotypical and functional differences between SKM\u2010BBz and SKM\u201028z CAR\u2010T cells. In conclusion, we developed novel SKM9\u20102\u2010derived CAR\u2010T cells with the 4\u20101BB costimulatory domain, which could provide a promising therapeutic approach against refractory MM.<\/jats:p>","DOI":"10.1002\/ijc.34843","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T05:09:23Z","timestamp":1705036163000},"page":"1828-1841","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel chimeric antigen receptor\u2010expressing T cells targeting the malignant mesothelioma\u2010specific antigen sialylated <scp>HEG1<\/scp>"],"prefix":"10.1002","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1526-575X","authenticated-orcid":false,"given":"Taku","family":"Kouro","sequence":"first","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"},{"name":"Cancer Vaccine and Immunotherapy Center Kanagawa Cancer Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Higashijima","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Horaguchi","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"},{"name":"Cancer Vaccine and Immunotherapy Center Kanagawa Cancer Center  Yokohama Japan"},{"name":"Department of Pediatric Surgery Nihon University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunobu","family":"Mano","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"},{"name":"Cancer Vaccine and Immunotherapy Center Kanagawa Cancer Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rika","family":"Kasajima","sequence":"additional","affiliation":[{"name":"Molecular Pathology and Genetics Division Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihui","family":"Xiang","sequence":"additional","affiliation":[{"name":"Molecular Pathology and Genetics Division Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kishi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Academic Assembly University of Toyama  Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Hamana","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Academic Assembly University of Toyama  Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Cancer Biology Division Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetomo","family":"Himuro","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"},{"name":"Cancer Vaccine and Immunotherapy Center Kanagawa Cancer Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rieko","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Division of Cancer Therapy Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoutaro","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Division of Cancer Therapy Kanagawa Cancer Center Research Institute  Yokohama Japan"},{"name":"Department of Medical Technology &amp; Clinical Engineering Gunma University of Health and Welfare  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohzoh","family":"Imai","sequence":"additional","affiliation":[{"name":"Kanagawa Cancer Center Research Institute  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-8833","authenticated-orcid":false,"given":"Tetsuro","family":"Sasada","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Kanagawa Cancer Center Research Institute  Yokohama Japan"},{"name":"Cancer Vaccine and Immunotherapy Center Kanagawa Cancer Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0063-2016"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.161.6.2791"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103849"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45768"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20845"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1827.2005.01791.x"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/pin.13140"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001469"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.2.720"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.1.104"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3838"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03855-x"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32639"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3181ac6138"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-32534-8"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0451"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.07.013"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00530-z"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-5890(97)00144-2"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0186"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1905675116"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.247"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04390-6"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.006"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502606200"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35583-w"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abh0272"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.014"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aay8248"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0286783"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1995.tb00246.x"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400783"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.07.025"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.154.1.180"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2218"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-11-187"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.34843","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T09:09:48Z","timestamp":1710320988000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.34843"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,11]]},"references-count":41,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,5,15]]}},"alternative-id":["10.1002\/ijc.34843"],"URL":"https:\/\/doi.org\/10.1002\/ijc.34843","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,11]]},"assertion":[{"value":"2023-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}