Immune infiltration in TP53 missense mutant contributes to poor prognosis in hepatocellular carcinoma, unlike CTNNB1 mutations

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the deadliest cancer over the world. In this study, we aimed to determine the most critical molecular event in HCC patients with tumor protein p53 (TP53) or catenin beta 1 (CTNNB1) mutations, and to explore how these two mutations differ in their impact on HCC prognostication.

Methods

We performed an integrated comparative analysis of exome and transcriptome data from The Cancer Genome Atlas (TCGA) for HCC patients. Patient prognosis and correlation with the immune infiltration characteristics were performed. HCC cell line based in vitro experiments were also performed to validate the mechanistic insights.

Results

The 3-year progression-free survival (PFS) analysis of HCC patients with TP53 mutations indicated a significantly poorer clinical outcome compared to those with CTNNB1 mutations. Functional annotation of the TP53 mutant cohort revealed a substantial upregulation of genes associated with immune regulation, while the CTNNB1 mutant cohort displayed a prominent activation of metabolic pathways. Further comparative analysis and in vitro experiments showed that TP53 missense mutations activated the signal transducer and activator of transcription 3 (STAT3) signaling pathway, which fostered neutrophil infiltration and enhanced the enrichment of regulatory T (Treg) cells by secreting specific inflammatory molecules in the tumor microenvironment. Notably, treatment with a an STAT3 inhibitor suppressed the expression of these inflammatory molecules, underscoring how an immunosuppressive tumor microenvironment in the TP53 mutant cohort contributes to a poor prognosis.

Conclusion

Our study provides valuable insights, revealing that HCC patients with TP53 missense mutations exhibit a distinct immune profile associated with poorer clinical outcome compared to those with CTNNB1 mutations.