Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. T...

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Bibliographic Details
Published in:Cancers 2023-04, Vol.15 (8), p.2379
Main Authors: Nishida, Naoshi, Aoki, Tomoko, Morita, Masahiro, Chishina, Hirokazu, Takita, Masahiro, Ida, Hiroshi, Hagiwara, Satoru, Minami, Yasunori, Ueshima, Kazuomi, Kudo, Masatoshi
Format: Article
Language:English
Subjects:
Antigen presentation
Antigens
Bile ducts
Cancer
Cancer therapies
Chemotherapy
Cholangiocarcinoma
Cholangitis
Comparative analysis
DNA methylation
Drug therapy, Combination
Epigenetics
Fibroblast growth factor receptor 2
Gene expression
Gene mutations
Genes
Genetic aspects
Genomes
Genotype & phenotype
Health aspects
Hepatitis
Immune checkpoint inhibitors
Inflammation
Liver cancer
Lymphocytes
Medical prognosis
Metastasis
Methylation
Mutation
Phenotypes
Tumor microenvironment
Tumor-infiltrating lymphocytes
Tumors
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Summary:Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a "non-inflamed" tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation ( = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the "inflamed" group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern ( = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the "non-inflamed" tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15082379