CTNNB1 mutation suppresses infiltration of immune cells in hepatocellular carcinoma through miRNA-mediated regulation of chemokine expression

Abstract

Mutations in the CTNNB1 gene in hepatocellular carcinoma (HCC) are related to immune exclusion, and HCC patients with CTNNB1 mutations tend to be primarily resistant to anti-PD1 therapy. However, systemic evaluation of immune cell infiltration in HCC with mutant CTNNB1 is lacking, and the mechanism of immune exclusion resulting from CTNNB1 mutations remains unclear. Based on CTNNB1 mutation status in HCC, we investigated RNA and miRNA expression and infiltration of immune cells. Data downloaded from TCGA showed that HCC with CTNNB1 mutation had an increased expression of CTNNB1. HCC with CTNNB1 mutation showed a reduction in infiltration score as well as in abundance of certain kinds of immune cells, including CD4 naïve T cells, CD4+ T cells, Tex cells, Th2 cells, Tfh cells, B cells, macrophages, and NK cells. Furthermore, there were 13 chemokines downregulated among all the 14 differentially expressed chemokines (DE-CKs) in CTNNB1 mutants compared to those in the wild type. A positive correlation was found between the expression of DE-CKs and infiltration score, as well as infiltration level of 6 types of immune cells, namely B cells, CD8+ cells, CD4+ cells, macrophages, neutrophils, and dendritic cells. Additionally, 302 differentially expressed immune-related genes (DE-IRGs) were involved mainly in the human immune response and cytokine-cytokine receptor interaction. The target DE-IRGs of differentially expressed miRNAs (DE-miRNAs) were identified and used to construct a network with DE-miRNAs and DE-CKs. Overall, CTNNB1 mutation in HCC led to a decrease in chemokine expression and subsequent suppression of immune cell infiltration partly through regulating specific miRNA-IRG-CK axes, pointing to a potential combination of interference of Wnt/β-catenin signaling with immunotherapy in HCC with CTNNB1 mutation.