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

Autor: Takanori Hasegawa, Masashi Fujita, Hidewaki Nakagawa, Kazuaki Chayama, Shinya Hayami, Hiroko Tanaka, Satoru Miyano, Shu Shimada, Kazuhiro Kakimi, Kaoru Nakano, Masaki Ueno, Seiya Imoto, Hiroki Yamaue, Shinji Tanaka, Rui Yamaguchi, Kazuhiro Maejima, Atsushi Ono, Akihiro Fujimoto, Koji Arihiro, Hiroshi Aikata, Shuto Hayashi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Research paper
medicine.medical_treatment
lcsh:Medicine
Tumor-associated macrophage
0302 clinical medicine
GSEA
gene set enrichment analysis
Tumor Microenvironment
cHCC-ICC
combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma
lcsh:R5-920
ICC
intrahepatic cholangiocarcinoma
Liver Neoplasms
TME
tumor microenvironment
Immunosuppression
General Medicine
Middle Aged
ECM
extracellular matrix
medicine.anatomical_structure
Liver
HCV
hepatitis C virus
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Female
TAM
tumor-associated macrophage
Chemokines
Liver cancer
lcsh:Medicine (General)
ICGC
International Cancer Genome Consortium
FDR
false discovery rate
Regulatory T cell
WGS
whole genome sequencing
Treg
regulatory T cell
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
CNA
copy number alternation
Immune system
Cell Line
Tumor
medicine
Humans
Aged
Hepatitis
Tumor microenvironment
SNV
single nucleotide variant
lcsh:R
FPKM-UQ
fragments per kilobase of exon per million fragments mapped with upper quartile normalization
medicine.disease
HR
hazard ratio
CYT
cytolytic activity
CI
confidence interval
OR
odds ratio
INDEL
insertion and deletion
HBV
hepatitis B virus
030104 developmental biology
Cancer research
TCGA
The Cancer Genome Atlas
Tumor Escape
PCAWG
Pan-Cancer Analysis of Whole Genomes
Transcriptome
HCC
hepatocellular carcinoma
Transcription Factors
Zdroj: EBioMedicine, Vol 53, Iss, Pp-(2020)
EBioMedicine
ISSN: 2352-3964
Popis: 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
Databáze: OpenAIRE
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