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      Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations

      research-article
      Author(s): a , b , c , d , e , b , a , a , a , f , g , g , h , h , b , b , c , h , g , i , j , d , c , a , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: Liver cancer, Tumor microenvironment, Tumor-associated macrophage, Regulatory T cell, TAM, tumor-associated macrophage, Treg, regulatory T cell, TME, tumor microenvironment, HCV, hepatitis C virus, HBV, hepatitis B virus, HCC, hepatocellular carcinoma, ICC, intrahepatic cholangiocarcinoma, cHCC-ICC, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma, WGS, whole genome sequencing, ICGC, International Cancer Genome Consortium, FPKM-UQ, fragments per kilobase of exon per million fragments mapped with upper quartile normalization , CYT, cytolytic activity, CNA, copy number alternation, PCAWG, Pan-Cancer Analysis of Whole Genomes, HR, hazard ratio, CI, confidence interval, OR, odds ratio, GSEA, gene set enrichment analysis, ECM, extracellular matrix, FDR, false discovery rate, SNV, single nucleotide variant, INDEL, insertion and deletion, TCGA, The Cancer Genome Atlas

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          Abstract

          Background

          The tumor microenvironment can be classified into immunologically active “inflamed” tumors and inactive “non-inflamed” tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy.

          Methods

          We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing.

          Findings

          Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells.

          Interpretation

          Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer.

          Funding

          The Japan Agency for Medical Research and Development (AMED).

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          Most cited references27

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          • Article: found

          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

          (2017)
          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
          Article 0 comments Cited 914 times – based on 0 reviews     Review now
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            Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.

            Yujin Hoshida, Sebastian M B Nijman, Masahiro Kobayashi … (2009)
            Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease.
            Article 0 comments Cited 434 times – based on 0 reviews     Review now
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              Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.

              Qiang Gao, Shuang-Jian Qiu, Jia Fan … (2007)
              To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.
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                Author and article information

                Contributors
                Masashi Fujita
                Rui Yamaguchi
                Takanori Hasegawa
                Shu Shimada
                Koji Arihiro
                Shuto Hayashi
                Kazuhiro Maejima
                Kaoru Nakano
                Akihiro Fujimoto
                Atsushi Ono
                Hiroshi Aikata
                Masaki Ueno
                Shinya Hayami
                Hiroko Tanaka
                Satoru Miyano
                Hiroki Yamaue
                Kazuaki Chayama
                Kazuhiro Kakimi
                Shinji Tanaka
                Seiya Imoto
                Hidewaki Nakagawa
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 26 February 2020
                Publication date Collection: March 2020
                Publication date (Electronic): 26 February 2020
                Volume: 53
                Electronic Location Identifier: 102659
                Affiliations
                [a ]Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
                [b ]Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
                [c ]Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
                [d ]Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
                [e ]Department of Anatomical Pathology, Hiroshima University, Hiroshima, Japan
                [f ]Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
                [g ]Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
                [h ]Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
                [i ]Department of Immuno-therapeutics, The University of Tokyo Hospital, Japan
                [j ]Cancer Immunology Data Multi-level Integration Unit, RIKEN Medical Innovation Hub Program, Tokyo, Japan
                Author notes
                [* ]Corresponding author. hidewaki@ 123456riken.jp
                Article
                Publisher ID: S2352-3964(20)30034-7 Publisher ID: 102659
                DOI: 10.1016/j.ebiom.2020.102659
                PMC ID: 7048625
                PubMed ID: 32113157
                SO-VID: cd83ceb5-13df-4b52-a351-d29b118caef9
                Copyright © © 2020 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 30 September 2019
                Date revision received : 21 January 2020
                Date accepted : 22 January 2020
                Categories
                Subject: Research paper

                Keywords: liver cancer,tumor microenvironment,tumor-associated macrophage,regulatory t cell,tam, tumor-associated macrophage,treg, regulatory t cell,tme, tumor microenvironment,hcv, hepatitis c virus,hbv, hepatitis b virus,hcc, hepatocellular carcinoma,icc, intrahepatic cholangiocarcinoma,chcc-icc, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma,wgs, whole genome sequencing,icgc, international cancer genome consortium,fpkm-uq, fragments per kilobase of exon per million fragments mapped with upper quartile normalization,cyt, cytolytic activity,cna, copy number alternation,pcawg, pan-cancer analysis of whole genomes,hr, hazard ratio,ci, confidence interval,or, odds ratio,gsea, gene set enrichment analysis,ecm, extracellular matrix,fdr, false discovery rate,snv, single nucleotide variant,indel, insertion and deletion,tcga, the cancer genome atlas
                Data availability:
                Keywords: liver cancer, tumor microenvironment, tumor-associated macrophage, regulatory t cell, tam, tumor-associated macrophage, treg, regulatory t cell, tme, tumor microenvironment, hcv, hepatitis c virus, hbv, hepatitis b virus, hcc, hepatocellular carcinoma, icc, intrahepatic cholangiocarcinoma, chcc-icc, combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma, wgs, whole genome sequencing, icgc, international cancer genome consortium, fpkm-uq, fragments per kilobase of exon per million fragments mapped with upper quartile normalization, cyt, cytolytic activity, cna, copy number alternation, pcawg, pan-cancer analysis of whole genomes, hr, hazard ratio, ci, confidence interval, or, odds ratio, gsea, gene set enrichment analysis, ecm, extracellular matrix, fdr, false discovery rate, snv, single nucleotide variant, indel, insertion and deletion, tcga, the cancer genome atlas

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