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Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma.

Abstract：

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.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Dong LQ,Peng LH,Ma LJ,Liu DB,Zhang S,Luo SZ,Rao JH,Zhu HW,Yang SX,Xi SJ,Chen M,Xie FF,Li FQ,Li WH,Ye C,Lin LY,Wang YJ,Wang XY,Gao DM,Zhou H,Yang HM,Wang J,Zhu SD,Wang XD,Cao Y,Zhou J,Fan J,Wu K,Gao

doi

10.1016/j.jhep.2019.12.014

subject

Has Abstract

pub_date

2020-05-01 00:00:00

pages

896-908

issue

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(19)30759-7

journal_volume

pub_type

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Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma.