Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma

doi:10.1016/j.jhep.2019.12.014

	Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma
	Dong, Liang-qing 7,8; Peng, Li-hua 9; Ma, Li-jie 7,8; Liu, Dong-bing 9,10; Zhang, Shu 7,8; Luo, Shu-zhen 9; Rao, Jun-hua 9; Zhu, Hong-wen 12,13; Yang, Shuai-xi 7,8; Xi, Shui-jun 7,8
刊名	JOURNAL OF HEPATOLOGY
	2020-05-01
卷号	72 期号:5 页码:896-908
关键词	Hepatocellular carcinoma Tumor heterogeneity Tumor microenvironment Immunoediting Neoantigen
ISSN号	0168-8278
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.
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关键词	PD-1 BLOCKADE ; CANCER ; EXPRESSION ; TISSUE ; SENSITIVITY
WOS研究方向	Gastroenterology & Hepatology
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000528847500020
内容类型	期刊论文
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.Chinese Acad Sci, CAS Key Lab Syst Biol, Innovat Ctr Cell Signaling Network,Shanghai Inst, CAS Enter Excellence Mol Cell Sci,Inst Biochem &, Shanghai, Peoples R China 2.James D Watson Inst Genome Sci, Hangzhou 310058, Peoples R China 3.Fudan Univ, Shanghai Inst Clin Bioinformat, Zhongshan Hosp, Shanghai 200032, Peoples R China 4.Univ Copenhagen, Dept Biol, DK-2200 Copenhagen N, Denmark 5.Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China 6.Fudan Univ, Key Lab Med Epigenet & Metab, Inst Biomed Sci, Shanghai 200032, Peoples R China 7.Fudan Univ, Dept Liver Surg & Transplantat, Liver Canc Inst, Zhongshan Hosp, 180 Fenglin Rd, Shanghai 200032, Peoples R China 8.Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Minist Educ, Shanghai 200032, Peoples R China 9.BGI Shenzhen, Shenzhen 518083, Peoples R China 10.BGI Shenzhen, Guangdong Prov Key Lab Human Dis Genom, Shenzhen Key Lab Genom, Shenzhen 518083, 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.