Abstract 2160: Immune escape mutations in HLA Class I, B2M and CASP8 genes shape tumor evolution

Abstract

Abstract The immune system has several mechanisms to recognize tumor cells as foreign and eliminate them. Somatically altered genes can create peptides, or neoantigens, that class I HLA (HLA-I) molecules can present to cytotoxic T-cells. As a result, people with suppressed immune systems commonly have a higher rate of cancer. PanCancer data of 9423 tumor exomes from the Cancer Genome Atlas project identified 299 frequently mutated cancer genes, 4 of which (HLA-A, HLA-B, beta-2-microglobulin (B2M), and caspase-8 (CASP8) are associated with the neoantigen presentation system. By mutating genes essential to immune recognition and cytotoxicity, tumors can escape the immune system. Tumors with a high mutation burden (MB) and thus more neoantigens experience even greater pressure to mutate HLA-I genes to escape detection. Therefore, the immune system shapes tumor evolution. Tumors with a higher mutation burden respond more effectively to immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-CTLA-4 drugs. However, there are many PD-L1 positive patients who fail to respond. These patients may have immune escape (IE) mutations inhibiting neoantigen presentation to T-cells, and a database of immune escape mutations would help inform cancer treatment and improve response to immunotherapy. From the TCGA Pan-Cancer dataset we identified samples with mutations in HLA-A, HLA-B, HLA-C and mutations or loss of B2M or CASP8. We also identified samples with microsatellite instability (MSI) and mutations in DNA Polymerase E (POLE), both of which are associated with high mutation burden. We predicted individual HLA genotypes using multiple programs and aligned tumor and normal reads to these alleles, and called mutations. We used the Integrative Genome Viewer, to validate the mutations and used multiple programs to identify potential functional effects of missense mutations. Finally, we used chi-squared tests to find associations between genes and phenotypes. There were substantially more mutations in HLA-A and HLA-B genes than in HLA-C. Loss-of-function (LoF) mutations accounted for over 50% of the mutations in HLA-A and 54% in HLA-B, but are significantly suppressed (25%) in HLA-C (X2=21; P=3 × 10-5). Since all HLA-C alleles are ligands for natural killer (NK) cell receptors (KIR) this indicates that NK cell recognition of tumor cells is important. Over 90% of HLA-I missense variants were predicted to be functional (likely to impact the stability, membrane localization, B2M binding, peptide binding of the protein, the signal peptide or T cell recognition). Cervical, head and neck, stomach, colon and lung cancer have the highest level of IE mutations (9-20%). Immune escape mutations were significantly higher in MSI (45%) and POLE mutated (72%) tumors as compared to MSI- and POLE wild type tumors (3.9%, X2=470 P<<0.0001). An increased knowledge of these IE mutations can be useful in identifying tumor or patient subsets that may respond better to ICI therapies. Citation Format: Megan Ren, Mathias Viard, Arman Bashirova, Meredith Yeager, Lisa Mirabello, Mary Carrington, Michael Dean. Immune escape mutations in HLA Class I, B2M and CASP8 genes shape tumor evolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2160.