Elsevier

EBioMedicine

Volume 53, March 2020, 102659
EBioMedicine

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

https://doi.org/10.1016/j.ebiom.2020.102659Get rights and content
Under a Creative Commons license
open access

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).

Keywords

Liver cancer
Tumor microenvironment
Tumor-associated macrophage
Regulatory T cell

Abbreviations

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

Cited by (0)