TP53gain-of-function mutation modulates the immunosuppressive microenvironment in non-HPV-associated oral squamous cell carcinoma

Abstract

BackgroundTP53, the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. SomaticTP53mutations occur in high frequencies in head and neck cancers, including oral squamous cell carcinoma (OSCC). Our study aims to understand the role ofTP53gain-of-function mutation in modulating the tumor immune microenvironment (TIME) in OSCC.MethodsShort hairpin RNA knockdown of mutantp53R172Hin syngeneic oral tumors demonstrated changes in tumor growth between immunocompetent and immunodeficient mice. HTG EdgeSeq targeted messenger RNA sequencing was used to analyze cytokine and immune cell markers in tumors with inactivated mutantp53R172H. Flow cytometry and multiplex immunofluorescence (mIF) confirmed the role of mutantp53R172Hin the TIME. The gene expression of patients with OSCC was analyzed by CIBERSORT and mIF was used to validate the immune landscape at the protein level.ResultsMutantp53R172Hcontributes to a cytokine transcriptome network that inhibits the infiltration of cytotoxic CD8+T cells and promotes intratumoral recruitment of regulatory T cells and M2 macrophages. Moreover,p53R172Halso regulates the spatial distribution of immunocyte populations, and their distribution between central and peripheral intratumoral locations. Interestingly,p53R172H-mutated tumors are infiltrated with CD8+and CD4+T cells expressing programmed cell death protein 1, and these tumors responded to immune checkpoint inhibitor and stimulator of interferon gene 1 agonist therapy. CIBERSORT analysis of human OSCC samples revealed associations between immune cell populations and theTP53R175Hmutation, which paralleled the findings from our syngeneic mouse tumor model.ConclusionsThese findings demonstrate that syngeneic tumors bearing theTP53R172Hgain-of-function mutation modulate the TIME to evade tumor immunity, leading to tumor progression and decreased survival.

Machine learning developed a macrophage signature for predicting prognosis, immune infiltration and immunotherapy features in head and neck squamous cell carcinoma

“…TP53, as the gene with the highest mutation frequency in human cancer, plays an important role in inducing cell apoptosis, aging, cell cycle arrest, and DNA damage repair, and is associated with increased chromosomal instability [42,43]. Previous studies have shown that TP53 mutations can increase the expression of relevant immune checkpoint molecules, and inhibit the in ltration of cytotoxic CD8 + T cells, leading to immunosuppressive states that induce macrophage polarization towards the M2 phenotype of TAMs, resulting in sustained tumor progression and a higher mutation frequency in high-risk groups [44]. TTN mutations can cause varied gene expression in cancers, boost tumor immune response, and increase susceptibility to immunotherapy [45].…”

Pinpointing the decisive role of TP53 mutations in orchestrating immunosuppression in head and neck squamous cell carcinoma

“…As for the underlying mechanisms, one hypothesis is that the mutant p53 could instigate the production of immunosuppressive cytokines while simultaneously suppressing proin ammatory factors. Shi et al found that the occurrence of TP53 mutations triggered a complex network of cytokine production, which obstructed the in ltration of cytotoxic CD8 + T cells while facilitating the accumulation of regulatory T cells (Tregs) and M2 macrophages within the oral squamous cell carcinoma (OSCC) tumor site 79 . Speci cally, the cytokine IFN-I 80 , IL6 81 and TGF-β 82 were reported to be responsive with TP53 mutations, hence in uencing tumor immune response.…”

Dissecting microRNA-regulated networks in hepatocellular carcinoma cell subtypes with different mutational profiles: Evidence from in vitro and in silico studies

“…Hepatocellular carcinoma (HCC) is a type of carcinoma affecting functional hepatocytes of epithelial origin (Feng et TP53 is a major tumor suppressor gene commonly mutated in many cancers (Ruijs et al 2010;Giacomelli et al 2018;Marei et al 2021). Mutation of this gene can result in both loss-of-function (Wang et al 2024) and gain-of-function effects (Shi et al 2023;Liu et al 2023). Studies have reported that mutations in speci c codons of TP53 can result in a mutant protein with a dominant negative effect on the wild-type protein, rendering the wild-type protein ineffective in its functions (Monti et al 2011).…”