Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities
文献类型：期刊论文
| 作者 | Lin, Jian11; Dai, Yuting10; Sang, Chen9; Song, Guohe9; Xiang, Bin8; Zhang, Mao9; Dong, Liangqing9; Xia, Xiaoli10; Ma, Jiaqiang9; Shen, Xia11 |
| 刊名 | JOURNAL FOR IMMUNOTHERAPY OF CANCER
 |
| 出版日期 | 2022-07-01 |
| 卷号 | 10期号:7页码:14 |
| 关键词 | tumor microenvironment cytotoxicity immunologic drug therapy combination |
| DOI | 10.1136/jitc-2022-004892 |
| 通讯作者 | Zhou, Hu(zhouhu@simm.ac.cn) ; Gao, Daming(dgao@sibcb.ac.cn) ; Gao, Qiang(gaoqiang@fudan.edu.cn) |
| 英文摘要 | 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. |
| WOS关键词 | HEPATOCELLULAR-CARCINOMA ; T-CELLS ; INFLAMMATION ; PHENOTYPES ; SIGNATURES ; INFECTION ; TARGETS ; MODEL |
| 资助项目 | National Natural Science Foundation of China[82130077] ; National Natural Science Foundation of China[81961128025] ; National Natural Science Foundation of China[82103314] ; Science and Technology Commission of Shanghai Municipality[20JC1418900] ; Science and Technology Commission of Shanghai Municipality[19XD1420700] ; Jinshan Hospital Flexible Mobile Talent Research Startup Fund[RXRC-2020-1] ; China Postdoctoral Science Foundation[2020M681181] |
| WOS研究方向 | Oncology ; Immunology |
| 语种 | 英语 |
| 出版者 | BMJ PUBLISHING GROUP |
| WOS记录号 | WOS:000830477500002 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302034]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhou, Hu; Gao, Daming; Gao, Qiang |
| 作者单位 | 1.Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai, Peoples R China 4.Fudan Univ, Inst Biomed Sci, Key Lab Med Epigenet & Metab, Shanghai, Peoples R China 5.Baylor Coll Med, Lester & Sue Smith Breast Ctr, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA 6.Univ Chinese Acad Sci, Ctr Microbes Dev & Hlth, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai, Peoples R China 7.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Gastroenterol & Hepatol, Sch Med, Shanghai, Peoples R China 8.Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Key Lab Computat Biol, Shanghai, Peoples R China 9.Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Dept Liver Surg & Transplantat,Minist Educ,Key La, Shanghai, Peoples R China 10.Shanghai Jiao Tong Univ, Ruijin Hosp, Natl Res Ctr Translat Med Shanghai, Shanghai Inst Hematol,Sch Med,State Key Lab Med G, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lin, Jian,Dai, Yuting,Sang, Chen,et al. Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2022,10(7):14. |
| APA | Lin, Jian.,Dai, Yuting.,Sang, Chen.,Song, Guohe.,Xiang, Bin.,...&Gao, Qiang.(2022).Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities.JOURNAL FOR IMMUNOTHERAPY OF CANCER,10(7),14. |
| MLA | Lin, Jian,et al."Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities".JOURNAL FOR IMMUNOTHERAPY OF CANCER 10.7(2022):14. |
入库方式： OAI收割
来源：上海药物研究所
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