PMID- 31887370
OWN - NLM
STAT- MEDLINE
DCOM- 20211006
LR  - 20221207
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 72
IP  - 5
DP  - 2020 May
TI  - Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal 
      hepatocellular carcinoma.
PG  - 896-908
LID - S0168-8278(19)30759-7 [pii]
LID - 10.1016/j.jhep.2019.12.014 [doi]
AB  - 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.
CI  - Copyright (c) 2019 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Dong, Liang-Qing
AU  - Dong LQ
AD  - 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 200032, China.
FAU - Peng, Li-Hua
AU  - Peng LH
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Ma, Li-Jie
AU  - Ma LJ
AD  - 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 200032, China.
FAU - Liu, Dong-Bing
AU  - Liu DB
AD  - BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of 
      Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, 
      Shenzhen 518083, China.
FAU - Zhang, Shu
AU  - Zhang S
AD  - 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 200032, China.
FAU - Luo, Shu-Zhen
AU  - Luo SZ
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Rao, Jun-Hua
AU  - Rao JH
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Zhu, Hong-Wen
AU  - Zhu HW
AD  - Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi 
      Road, Shanghai 201203, China.
FAU - Yang, Shuai-Xi
AU  - Yang SX
AD  - 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 200032, China.
FAU - Xi, Shui-Jun
AU  - Xi SJ
AD  - 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 200032, China.
FAU - Chen, Min
AU  - Chen M
AD  - CAS Key Laboratory of Systems Biology, Innovation Center for Cell Signaling 
      Network, CAS enter for Excellence in Molecular Cell Science, Institute of 
      Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, 
      Chinese Academy of Sciences, Shanghai, China.
FAU - Xie, Fan-Fan
AU  - Xie FF
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Li, Fu-Qiang
AU  - Li FQ
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Li, Wen-Hui
AU  - Li WH
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Ye, Chen
AU  - Ye C
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Lin, Li-Ya
AU  - Lin LY
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Wang, Yu-Jue
AU  - Wang YJ
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Wang, Xiao-Ying
AU  - Wang XY
AD  - 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 200032, China.
FAU - Gao, Da-Ming
AU  - Gao DM
AD  - CAS Key Laboratory of Systems Biology, Innovation Center for Cell Signaling 
      Network, CAS enter for Excellence in Molecular Cell Science, Institute of 
      Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, 
      Chinese Academy of Sciences, Shanghai, China.
FAU - Zhou, Hu
AU  - Zhou H
AD  - Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi 
      Road, Shanghai 201203, China.
FAU - Yang, Huan-Ming
AU  - Yang HM
AD  - BGI-Shenzhen, Shenzhen 518083, China; James D. Watson Institute of Genome 
      Sciences, Hangzhou 310058, China.
FAU - Wang, Jian
AU  - Wang J
AD  - BGI-Shenzhen, Shenzhen 518083, China; James D. Watson Institute of Genome 
      Sciences, Hangzhou 310058, China.
FAU - Zhu, Shi-da
AU  - Zhu SD
AD  - BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of 
      Copenhagen, Copenhagen N DK-2200, Denmark.
FAU - Wang, Xiang-Dong
AU  - Wang XD
AD  - Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan 
      University, Shanghai 200032, China.
FAU - Cao, Ya
AU  - Cao Y
AD  - Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, 
      Xiangya Hospital, Central South University, Changsha 410078, China.
FAU - Zhou, Jian
AU  - Zhou J
AD  - 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 200032, China; Key Laboratory 
      of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan 
      University, Shanghai 200032, China.
FAU - Fan, Jia
AU  - Fan J
AD  - 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 200032, China; Key Laboratory 
      of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan 
      University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, 
      Fudan University, Shanghai 200433, China.
FAU - Wu, Kui
AU  - Wu K
AD  - BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of 
      Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, 
      Shenzhen 518083, China; Department of Biology, University of Copenhagen, 
      Copenhagen N DK-2200, Denmark. Electronic address: wukui@genomics.cn.
FAU - Gao, Qiang
AU  - Gao Q
AD  - 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 200032, China; Key Laboratory 
      of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan 
      University, Shanghai 200032, China. Electronic address: gaoqiang@fudan.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191227
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (HLA Antigens)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antigens, Neoplasm/genetics
MH  - Biomarkers, Tumor/genetics
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Carcinoma, Hepatocellular/*genetics/*immunology
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - HLA Antigens/genetics
MH  - Humans
MH  - Liver Neoplasms/*genetics/*immunology
MH  - Lymphocytes, Tumor-Infiltrating/immunology
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Neoplasm Recurrence, Local
MH  - Neoplasms, Multiple Primary/*genetics/*immunology
MH  - Receptors, Antigen, T-Cell/genetics
MH  - Transcriptome
MH  - *Tumor Escape
MH  - Exome Sequencing
OTO - NOTNLM
OT  - Hepatocellular carcinoma
OT  - Immunoediting
OT  - Neoantigen
OT  - Tumor heterogeneity
OT  - Tumor microenvironment
COIS- Conflict of interest The authors declare no conflicts of interest that pertain to 
      this work. Please refer to the accompanying ICMJE disclosure forms for further 
      details.
EDAT- 2019/12/31 06:00
MHDA- 2021/10/07 06:00
CRDT- 2019/12/31 06:00
PHST- 2019/05/01 00:00 [received]
PHST- 2019/10/29 00:00 [revised]
PHST- 2019/12/03 00:00 [accepted]
PHST- 2019/12/31 06:00 [pubmed]
PHST- 2021/10/07 06:00 [medline]
PHST- 2019/12/31 06:00 [entrez]
AID - S0168-8278(19)30759-7 [pii]
AID - 10.1016/j.jhep.2019.12.014 [doi]
PST - ppublish
SO  - J Hepatol. 2020 May;72(5):896-908. doi: 10.1016/j.jhep.2019.12.014. Epub 2019 Dec 
      27.