Abstract PO022: Somatic mutations in tumor infiltrating lymphocytes can affect the expression of immune system genes in the tumor microenvironment

Abstract

Abstract Avoiding immune destruction is an emerging hallmark of cancer. It includes tumor cell mutations and epigenetic modifications that allow tumor cells to either evade detection by the immune system, or render the immune response ineffective. However, mutations in tumor infiltrating lymphocytes that inhibit immune response to tumor growth, have not been specifically identified as a hallmark of cancer. We have identified four distinct somatic mutations in tumor infiltrating lymphocytes that affect the expression of immune system genes in tumor samples, suggesting that these lymphocytic mutation may cause a deficient immune response, contributing to cancer progression. These rare mutations occurred frequently in specific cancer types. The T292Nfs*18 mutation in the FETUB gene, R216Gfs*20 in CCDC43, N377D in CLEC4M and V78Gfs*46 in RAB11FIP4 occurred in 13% of breast invasive carcinoma, 41% of colon adenocarcinoma, 12% of ovarian cystadenocarcinoma (OV) and 16% of OV samples respectively, compared to 0.002%, 0.003%, 0.014% and 0.001% in aggregated variant databases. These variants were found in 7-20% of DNA sequences in both tumor and matched normal blood samples, indicating that they originated in tumor infiltrating lymphocytes, rather than in the tumor cells. We argue that these mutations are unlikely to be passenger mutations since each of them occur in only 0-2% of normal tissue samples and in less than 2% of tumor samples from 24-32 of 32 cancer types other than the one noted above for each of the four mutations. The set of differentially expressed genes (FDR<0.05) in samples with each of the four variants, compared to samples without the variant, included 22-445 genes associated with the immune system pathway, suggesting a possible mechanism by which these mutations may affect tumor growth. Given the myriad of diverse mechanisms and genes implicated in cancer, it is not unexpected that mutations in tumor infiltrating lymphocytes could contribute to cancer progression. With further validation, genetic lesions in tumor infiltrating lymphocytes may represent a previously unstudied mechanism affecting tumor growth, and a new class of therapeutic targets. These mutations may also represent potential “somatic” risk markers that may present with age, supplementing traditional germline risk markers. Citation Format: Ramu Anandakrishnan, Robin T. Varghese, Nicholas A. Kinney, Harold R. Garner. Somatic mutations in tumor infiltrating lymphocytes can affect the expression of immune system genes in the tumor microenvironment [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO022.