Abstract 548: Exploiting pronounced selection pressure from therapeutic bottlenecks to identify orthogonal immunotherapy targets

Abstract

Abstract Evolutionary processes play a crucial role in the development of cancer, where tumor cells continuously adapt, leading to the dominance of cell populations over their non-tumor counterparts, evading treatment and ultimately resulting in death. Effective cancer therapies induce significant and targeted selection pressures. During and in response to the induced bottleneck by therapy, the heterogeneous cancer cell population either diminishes or evolves, causing a subsequent selective sweep and the emergence of cells with resistance traits. However, this bottleneck phase presents a unique opportunity to predictably reduce the diversity of tumor cells. In this context, we propose a framework to quantify the selection on variants before, during, and after the therapeutic bottleneck, enhancing our understanding of the mechanisms underlying the acquisition of therapeutic resistance. Furthermore, we combine measures of selection intensity with the prediction of neoantigens in a patient cohort to identify potential alternative targets for immunotherapy. The outcome is a strategy that exploits the predictability introduced by the primary therapeutic bottleneck to eliminate the remaining tumor cell population. Finally, we illustrate the efficacy of this strategy in the context of several cancer types and empirically identify potential cancer type specific and pan-cancer immunotherapy targets orthogonal to primary, first-line therapies. Citation Format: J. Nic Fisk, Jeffrey P. Townsend. Exploiting pronounced selection pressure from therapeutic bottlenecks to identify orthogonal immunotherapy targets [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 548.