Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma
文献类型:期刊论文
作者 | Dong, Liang-qing6,7; Peng, Li-hua8; Ma, Li-jie6,7; Liu, Dong-bing8,9; Zhang, Shu6,7; Luo, Shu-zhen8; Rao, Jun-hua8; Zhu, Hong-wen10,11; Yang, Shuai-xi6,7; Xi, Shui-jun6,7 |
刊名 | JOURNAL OF HEPATOLOGY |
出版日期 | 2020-05-01 |
卷号 | 72期号:5页码:896-908 |
ISSN号 | 0168-8278 |
关键词 | Hepatocellular carcinoma Tumor heterogeneity Tumor microenvironment Immunoediting Neoantigen |
DOI | 10.1016/j.jhep.2019.12.014 |
通讯作者 | Wu, Kui(wukui@genomics.cn) ; Gao, Qiang(gaoqiang@fudan.edu.cn) |
英文摘要 | Background & Aims: The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. Methods: We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions. Results: IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038). Conclusion: Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC. Lay summary: Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC. (c) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
WOS关键词 | PD-1 BLOCKADE ; CANCER ; EXPRESSION ; TISSUE ; SENSITIVITY |
资助项目 | National Natural Science Foundation of China[91859105] ; National Natural Science Foundation of China[81572292] ; National Natural Science Foundation of China[81572367] ; Basic Research Project from Technology Commission of Shanghai Municipality[17JC1402200] ; National Science and Technology Major Project of China[2018ZX10302205-003] ; National Science and Technology Major Project of China[2017ZX10203208-004] ; Science, Technology and Innovation Commission of Shenzhen Municipality[JSGG20170412153009953] |
WOS研究方向 | Gastroenterology & Hepatology |
语种 | 英语 |
出版者 | ELSEVIER |
WOS记录号 | WOS:000528847500020 |
源URL | [http://119.78.100.183/handle/2S10ELR8/280520] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Wu, Kui; Gao, Qiang |
作者单位 | 1.Fudan Univ, Key Lab Med Epigenet & Metab, Inst Biomed Sci, Shanghai 200032, Peoples R China 2.Univ Copenhagen, Dept Biol, DK-2200 Copenhagen N, Denmark 3.Fudan Univ, Shanghai Inst Clin Bioinformat, Zhongshan Hosp, Shanghai 200032, Peoples R China 4.Cent South Univ, Key Lab Carcinogenesis & Invas, Chinese Minist Educ, Xiangya Hosp, Changsha 410078, Peoples R China 5.Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China 6.Fudan Univ, Dept Liver Surg & Transplantat, Liver Canc Inst, Zhongshan Hosp, 180 Fenglin Rd, Shanghai 200032, Peoples R China 7.Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Minist Educ, Shanghai 200032, Peoples R China 8.BGI Shenzhen, Shenzhen 518083, Peoples R China 9.BGI Shenzhen, Guangdong Prov Key Lab Human Dis Genom, Shenzhen Key Lab Genom, Shenzhen 518083, Peoples R China 10.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
推荐引用方式 GB/T 7714 | Dong, Liang-qing,Peng, Li-hua,Ma, Li-jie,et al. Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma[J]. JOURNAL OF HEPATOLOGY,2020,72(5):896-908. |
APA | Dong, Liang-qing.,Peng, Li-hua.,Ma, Li-jie.,Liu, Dong-bing.,Zhang, Shu.,...&Gao, Qiang.(2020).Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma.JOURNAL OF HEPATOLOGY,72(5),896-908. |
MLA | Dong, Liang-qing,et al."Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma".JOURNAL OF HEPATOLOGY 72.5(2020):896-908. |
入库方式: OAI收割
来源:上海药物研究所
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