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.