Abstract
The tumor immune microenvironment (TIME) of head and neck squamous cell carcinomas (HNSCC) and other solid malignancies is a key determinant of therapy response and prognosis. Among other factors, it is shaped by the tumor mutational burden and defects in DNA repair enzymes. Based on the TCGA database we aimed to define specific, altered genes associated with different TIME types, which might represent new predictive markers or targets for immuno-therapeutic approaches. The HNSCC cohort of the TCGA database was used to define 3 TIME types (immune-activated, immune-suppressed, immune-absent) according to expression of immune-related genes. Mutation frequencies were correlated to the 3 TIME types. Overall survival was best in the immune-activated group. 9 genes were significantly differentially mutated in the 3 TIME types with strongest differences for TP53 and the histone-acetyltransferase EP300. Mutations in EP300 correlated with an immune-activated TIME. In panCancer analyses anti-tumor immune activity was increased in EP300 mutated esophageal, stomach and prostate cancers. Downregulation of EP300 gene expression was associated with higher anti-tumor immunity in most solid malignancies. Since EP300 is a promoter of glycolysis, which negatively affects anti-tumor immune response, we analyzed the association of EP300 with tumor metabolism. PanCancer tumor metabolism was strongly shifted towards oxidative phosphorylation in EP300 downregulated tumors. In silico analyses of of publicly available in vitro data showed a decrease of glycolysis-associated genes after treatment with the EP300 inhibitor C646. Our study reveals associations of specific gene alterations with different TIME types. In detail, we defined EP300 as a panCancer inhibitor of the TIME most likely via metabolic modulation. In this context EP300 represents a promising predictive biomarker and an immuno-therapeutic target.
Highlights
The tumor immune microenvironment (TIME) has emerged as a critical factor determining prognosis and therapy response across most solid tumors
Tumor immune microenvironment subtypes in head and neck squamous cell carcinomas are associated with specific gene mutations
We started the evaluation with the creation of three TIME subtypes based on gene expression profiles of immune-related genes as outlined in Fig. 1A: 1. An immune-activated TIME with high expressions of genes involved in cytotoxic T cell response
Summary
The tumor immune microenvironment (TIME) has emerged as a critical factor determining prognosis and therapy response across most solid tumors In immunogenic tumors, such as breast and colon cancers or non-small cell lung cancers, the quantity and quality of tumor infiltrating lymphocytes has prognostic significance comparable to the TNM-classification[1]. In healthy persons these are only expressed by male germ line cells and are usually not presented by MHC to induce T cell tolerance during thymic maturation Another source of tumor antigens are oncogenic viruses, such as Human Papilloma Virus (HPV) or Epstein-Barr Virus (EBV), which can encode antigenic peptides. Over the last years tumor mutations (mostly non-synonymous point mutations) have been brought into focus as another source of tumor antigens These lead to modified peptide sequences (“mutational neoantigens”), which can induce a T cell response, when presented by MHC6. In this study we aimed to discover specific mutations associated with specific TIME profiles and constituting predictors for response to immune checkpoint inhibition or as potential adjuncts to improve efficacy of current immunotherapeutic agents
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