Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities
Background 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/7/e004892.full |
| _version_ | 1818512177971068928 |
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| author | Xiaoming Zhang Shu Zhang Bing Zhang Jian Zhou Hai Fang Jia Fan Mao Zhang Xiangdong Wang Qiang Gao Xia Shen Bin Xiang Yuting Dai Jian Lin Chen Sang Guohe Song Liangqing Dong Xiaoli Xia Jiaqiang Ma Shuyi Ji Mingjie Wang Hu Zhou Daming Gao |
| author_facet | Xiaoming Zhang Shu Zhang Bing Zhang Jian Zhou Hai Fang Jia Fan Mao Zhang Xiangdong Wang Qiang Gao Xia Shen Bin Xiang Yuting Dai Jian Lin Chen Sang Guohe Song Liangqing Dong Xiaoli Xia Jiaqiang Ma Shuyi Ji Mingjie Wang Hu Zhou Daming Gao |
| author_sort | Xiaoming Zhang |
| collection | DOAJ |
| description | Background 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.Methods We performed genomic, transcriptomic, and proteomic characterization of 255 paired iCCA and adjacent liver tissues. We validated our findings through H&E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10), in vitro functional studies, and in vivo transposon-based mouse models.Results 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 KRAS 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.Conclusions 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. |
| first_indexed | 2024-12-10T23:43:17Z |
| format | Article |
| id | doaj.art-7bd9341fb53b4bac8699b0d63b4d1f02 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-10T23:43:17Z |
| publishDate | 2022-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-7bd9341fb53b4bac8699b0d63b4d1f022022-12-22T01:28:59ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-07-0110710.1136/jitc-2022-004892Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilitiesXiaoming Zhang0Shu Zhang1Bing Zhang2Jian Zhou3Hai Fang4Jia Fan5Mao Zhang6Xiangdong Wang7Qiang Gao8Xia Shen9Bin Xiang10Yuting Dai11Jian Lin12Chen Sang13Guohe Song14Liangqing Dong15Xiaoli Xia16Jiaqiang Ma17Shuyi Ji18Mingjie Wang19Hu Zhou20Daming Gao21Department of Ultrasound, Inner Mongolia people’s hospital, Inner Mongolia, China1 Division of Epidemiology, Department of Health Informatics and Public Health, Tohoku University School of Public Health, Graduate School of Medicine, Sendai, Japan1 Psychiatry, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China1 China Center for Health Development Studies, Peking University, Beijing, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaAff1 grid.240145.60000000122914776The University of Texas MD Anderson Cancer Center Houston TX USAInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China1 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China1 Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK4Prospect Analytical, San Jose, California, USAShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People`s Republic of ChinaJinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, ChinaShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, ChinaJinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, ChinaDepartment of Gastroenterology & Hepatology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, ChinaBackground 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.Methods We performed genomic, transcriptomic, and proteomic characterization of 255 paired iCCA and adjacent liver tissues. We validated our findings through H&E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10), in vitro functional studies, and in vivo transposon-based mouse models.Results 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 KRAS 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.Conclusions 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.https://jitc.bmj.com/content/10/7/e004892.full |
| spellingShingle | Xiaoming Zhang Shu Zhang Bing Zhang Jian Zhou Hai Fang Jia Fan Mao Zhang Xiangdong Wang Qiang Gao Xia Shen Bin Xiang Yuting Dai Jian Lin Chen Sang Guohe Song Liangqing Dong Xiaoli Xia Jiaqiang Ma Shuyi Ji Mingjie Wang Hu Zhou Daming Gao Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities Journal for ImmunoTherapy of Cancer |
| title | Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities |
| title_full | Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities |
| title_fullStr | Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities |
| title_full_unstemmed | Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities |
| title_short | Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities |
| title_sort | multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities |
| url | https://jitc.bmj.com/content/10/7/e004892.full |
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