Abstract 1613: Evolution of mutations in the antigen presentation machinery across cancers

Abstract

Abstract Immune escape is a critical hallmark of cancer progression. Under immunosurveillance, a subset of cancer-associated antigens or neoantigens are presented to the cancer cell surface via the antigen presentation machinery (APM) for recognition by antigen-specific T cells. During clonal evolution, cancer cells can evade such immunosurveillance by suppressing or ablating the APM. The defects in APM can further cause resistance to cancer immunotherapies and is associated with worse prognosis. Understanding how the defects in APM emerge and further shape the evolution of cancers is critical for devising strategies to overcome such immune escape mechanisms. However, it is not known when mutations in the APM occur along the history of cancer clonal evolution. We utilized a molecular archeology of cancer approach to reconstruct the evolution history of mutations in APM across 38 cancer types using whole-genome sequencing data from PCAWG. Genetic alterations in the APM occur in nearly 30% of patients, with varying frequencies and associations with immune infiltration across cancer types. Employing a League model to compare the timing of genetic events, we found that APM mutations can be early clonal, late clonal, or subclonal along cancer development. Further examination of individual tumors identified driver mutations that can happen before or after APM mutations along cancer development. Our study reveals the evolution of APM mutations in different cancers in a genetic context-aware manner. This information can contribute to optimizing personalized immunotherapy. Citation Format: Wenjie Chen, Toby Baker, Zhihui Zhang, Peter Van Loo, Shengqing Stan Gu. Evolution of mutations in the antigen presentation machinery across cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1613.