Abstract PL04-01: The various layers of intratumor heterogeneity and their impact on tumor immunity

Abstract The current understanding in the immunotherapy field suggests that tumors with higher mutational loads present more neoantigens, thereby enhancing their immunogenicity. However, tumors with similar mutational burdens exhibit variable immune responses, and some cancers with low mutational loads can still respond to immunotherapy, challenging this association. Additionally, intra-tumor heterogeneity is recognized as a significant factor influencing immune surveillance. This talk will delve into the complex layers of intra-tumor heterogeneity, exploring how genomic, epigenetic, and neoantigen diversity impact immune response. Using novel comparative mouse models, we will examine the genomic effects of mutational load and intra-tumor heterogeneity on immune response. Furthermore, we will investigate how the canonical and non-canonical neopeptide landscape contributes to intra-tumor heterogeneity and its impact on tumor immunity. Our research also explores the untapped potential of cancer neopeptides, including those derived from intracellular microbial antigens and aberrant protein synthesis. As a proof of concept, we will discuss our recent study, which investigated how defective translation machinery components in cancer cells generate aberrant peptides, enhancing tumor immunogenicity and sensitivity to checkpoint blockade immunotherapy. Our findings suggest that inhibiting translation fidelity regulators could be a potent novel immunotherapy strategy, potentially leading to long-lasting anti-tumor control. By understanding and leveraging these mechanisms, we aim to redefine intra-tumor heterogeneity as both a barrier and a therapeutic opportunity, paving the way for more effective treatments. Citation Format: Yardena Samuels. The various layers of intratumor heterogeneity and their impact on tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr PL04-01.