{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:12Z","timestamp":1792787292024,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"unspecified","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["19XD1420700"],"award-info":[{"award-number":["19XD1420700"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["20JC1418900"],"award-info":[{"award-number":["20JC1418900"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2020M681181"],"award-info":[{"award-number":["2020M681181"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jinshan Hospital","award":["RXRC-2020-1"],"award-info":[{"award-number":["RXRC-2020-1"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81961128025"],"award-info":[{"award-number":["81961128025"]}],"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":["82103314"],"award-info":[{"award-number":["82103314"]}],"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":["82130077"],"award-info":[{"award-number":["82130077"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune microenvironment is well recognized as a critical regulator across cancer types, despite its complex roles in different disease conditions. Intrahepatic cholangiocarcinoma (iCCA) is characterized by a tumor-reactive milieu, emphasizing a deep insight into its immunogenomic profile to provide prognostic and therapeutic implications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed genomic, transcriptomic, and proteomic characterization of 255 paired iCCA and adjacent liver tissues. We validated our findings through H&amp;E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10),\n                      <jats:italic>in vitro<\/jats:italic>\n                      functional studies, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      transposon-based mouse models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Integrated multimodule data identified three immune subgroups with distinct clinical, genetic, and molecular features, designated as IG1 (immune-suppressive, 25.1%), IG2 (immune-exclusion, 42.7%), and IG3 (immune-activated, 32.2%). IG1 was characterized by excessive infiltration of neutrophils and immature dendritic cells (DCs). The hallmark of IG2 was the relatively higher tumor-proliferative activity and tumor purity. IG3 exhibited an enrichment of adaptive immune cells, natural killer cells, and activated DCs. These immune subgroups were significantly associated with prognosis and validated in two independent cohorts. Tumors with\n                      <jats:italic>KRAS<\/jats:italic>\n                      mutations were enriched in IG1 and associated with myeloid inflammation-dominated immunosuppression. Although tumor mutation burden was relatively higher in IG2, loss of heterozygosity in human leucocyte antigen and defects in antigen presentation undermined the recognition of neoantigens, contributing to immune-exclusion behavior. Pathological analysis confirmed that tumor-infiltrating lymphocytes and tertiary lymphoid structures were both predominant in IG3. Hepatitis B virus (HBV)-related samples tended to be under-represented in IG1, and scRNA-seq analyses implied that HBV infection indeed alleviated myeloid inflammation and reinvigorated antitumor immunity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study elucidates that the immunogenomic traits of iCCA are intrinsically heterogeneous among patients, posing great challenge and opportunity for the application of personalized immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-004892","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T11:26:31Z","timestamp":1658402791000},"page":"e004892","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":72,"title":["Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6457-7026","authenticated-orcid":false,"given":"Jian","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Sang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohe","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangqing","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqiang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7006-4737","authenticated-orcid":false,"given":"Hu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daming","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"2022072108252040000_10.7.e004892.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"2022072108252040000_10.7.e004892.2","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.jhep.2020.03.007","article-title":"Molecular targeted therapies: Ready for \"prime time\" in biliary tract\u00a0cancer","volume":"73","author":"Lamarca","year":"2020","journal-title":"J Hepatol"},{"key":"2022072108252040000_10.7.e004892.3","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001946"},{"key":"2022072108252040000_10.7.e004892.4","doi-asserted-by":"crossref","unstructured":"Shi G-M , Jian Z , Fan J , et al . Phase II study of lenvatinib in combination with GEMOX chemotherapy for advanced intrahepatic cholangiocarcinoma. Journal of Clinical Oncology 2021;39:e16163.doi:10.1200\/JCO.2021.39.15_suppl.e16163","DOI":"10.1200\/JCO.2021.39.15_suppl.e16163"},{"key":"2022072108252040000_10.7.e004892.5","unstructured":"Imfinzi plus chemotherapy significantly improved overall survival in 1st-line advanced biliary tract cancer in TOPAZ-1 phase III trial at interim analysis, 2021. Available: https:\/\/www.astrazeneca.com\/content\/astraz\/media-centre\/press releases\/2021\/imfinzi-improved-survival-in-biliary-tract-cancer.html"},{"key":"2022072108252040000_10.7.e004892.6","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.06.007"},{"key":"2022072108252040000_10.7.e004892.7","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002434"},{"key":"2022072108252040000_10.7.e004892.8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.12.005"},{"key":"2022072108252040000_10.7.e004892.9","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25890"},{"key":"2022072108252040000_10.7.e004892.10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.01.001"},{"key":"2022072108252040000_10.7.e004892.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.12.006"},{"key":"2022072108252040000_10.7.e004892.12","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31092"},{"key":"2022072108252040000_10.7.e004892.13","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/hep.32150","article-title":"The immunogenomic landscape of resected intrahepatic cholangiocarcinoma","volume":"75","author":"Carapeto","year":"2022","journal-title":"Hepatology"},{"key":"2022072108252040000_10.7.e004892.14"},{"key":"2022072108252040000_10.7.e004892.15","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.jhep.2021.07.016","article-title":"Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma","volume":"75","author":"Carpino","year":"2021","journal-title":"J Hepatol"},{"key":"2022072108252040000_10.7.e004892.16","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The molecular signatures database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"2022072108252040000_10.7.e004892.17","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.103"},{"key":"2022072108252040000_10.7.e004892.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.04.022"},{"key":"2022072108252040000_10.7.e004892.19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9971"},{"key":"2022072108252040000_10.7.e004892.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.04.004"},{"key":"2022072108252040000_10.7.e004892.21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01298"},{"key":"2022072108252040000_10.7.e004892.22","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3524"},{"key":"2022072108252040000_10.7.e004892.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1906-8"},{"key":"2022072108252040000_10.7.e004892.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0053-3"},{"key":"2022072108252040000_10.7.e004892.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2014.07.008"},{"key":"2022072108252040000_10.7.e004892.26","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1172\/JCI97953","article-title":"Role of prostanoids in gastrointestinal cancer","volume":"128","author":"Wang","year":"2018","journal-title":"J Clin Invest"},{"key":"2022072108252040000_10.7.e004892.27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00438"},{"key":"2022072108252040000_10.7.e004892.28","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.immuni.2020.10.020","article-title":"Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade","volume":"53","author":"Bonavita","year":"2020","journal-title":"Immunity"},{"key":"2022072108252040000_10.7.e004892.29","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.ccell.2020.06.002","article-title":"Immunogenomic landscape of hematological malignancies","volume":"38","author":"Dufva","year":"2020","journal-title":"Cancer Cell"},{"key":"2022072108252040000_10.7.e004892.30","doi-asserted-by":"publisher","DOI":"10.1101\/056101"},{"key":"2022072108252040000_10.7.e004892.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8399"},{"key":"2022072108252040000_10.7.e004892.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19288-6"},{"key":"2022072108252040000_10.7.e004892.33","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0368"},{"key":"2022072108252040000_10.7.e004892.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.03.012"},{"key":"2022072108252040000_10.7.e004892.35","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41586-019-1032-7","article-title":"Neoantigen-directed immune escape in lung cancer evolution","volume":"567","author":"Rosenthal","year":"2019","journal-title":"Nature"},{"key":"2022072108252040000_10.7.e004892.36","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0672"},{"key":"2022072108252040000_10.7.e004892.37","doi-asserted-by":"crossref","unstructured":"Wang J , Jiang D , Zheng X . Tertiary lymphoid structure and CD8 T cell exclusion in minimally invasive adenocarcinoma. medRxiv 2020.","DOI":"10.1101\/2020.08.03.20166991"},{"key":"2022072108252040000_10.7.e004892.38","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhep.2021.10.030","article-title":"Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma","volume":"76","author":"Ding","year":"2022","journal-title":"J Hepatol"},{"key":"2022072108252040000_10.7.e004892.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03362-0"},{"key":"2022072108252040000_10.7.e004892.40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41423-019-0306-1","article-title":"Myeloid immunosuppression and immune checkpoints in the tumor microenvironment","volume":"17","author":"Nakamura","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"2022072108252040000_10.7.e004892.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.03.008"},{"key":"2022072108252040000_10.7.e004892.42","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23153"},{"key":"2022072108252040000_10.7.e004892.43","doi-asserted-by":"crossref","first-page":"778","DOI":"10.3892\/mmr.2017.6630","article-title":"Upregulation of SOCS3 in lung CD4+ T cells in a mouse model of chronic PA lung infection and suppression of Th17\u2011mediated neutrophil recruitment in exogenous SOCS3 transfer in vitro","volume":"16","author":"Ding","year":"2017","journal-title":"Mol Med Rep"},{"key":"2022072108252040000_10.7.e004892.44","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1049"},{"key":"2022072108252040000_10.7.e004892.45","doi-asserted-by":"crossref","first-page":"17292","DOI":"10.18632\/oncotarget.14079","article-title":"Hepatitis B virus-associated intrahepatic cholangiocarcinoma: a malignancy of distinctive characteristics between hepatocellular carcinoma and intrahepatic cholangiocarcinoma","volume":"8","author":"Jeong","year":"2017","journal-title":"Oncotarget"},{"key":"2022072108252040000_10.7.e004892.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.04.024"},{"key":"2022072108252040000_10.7.e004892.47","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316510"},{"key":"2022072108252040000_10.7.e004892.48","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/j.1440-1746.2010.06305.x","article-title":"Hepatocellular carcinoma with persistent hepatitis B virus infection shows unusual downregulation of Ras expression and differential response to Ras mediated signaling","volume":"26","author":"Bose","year":"2011","journal-title":"J Gastroenterol Hepatol"},{"key":"2022072108252040000_10.7.e004892.49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800871"},{"key":"2022072108252040000_10.7.e004892.50","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.cell.2020.09.044","article-title":"Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients","volume":"183","author":"Kim","year":"2020","journal-title":"Cell"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-004892","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T11:26:48Z","timestamp":1658402808000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-004892"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,21]]},"published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1136\/jitc-2022-004892"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-004892","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7]]}}}