Abstract B022: Genetic evolution of immune escape across cancers

Abstract Immune escape is a critical hallmark of cancer, driving disease progression, poor prognosis, and resistance to therapies. However, how immune escape evolves in cancer is poorly understood. Existing studies are limited by a narrow focus on escape mechanisms and the inability of conventional methods to resolve the temporal order of clonal mutations. To overcome these challenges, we developed an integrative approach that combines systematic mining of immunomodulatory genes and novel computational reconstruction of tumor evolution history. Using this framework, we generated the first pan-cancer atlas of genetic evolution of immune escape. We find that immunomodulatory pathways are mutated at varying frequencies across cancers. For example, antigen presentation machinery is highly mutated in chromophobe renal cell carcinoma and lung squamous cell carcinoma, while the protein methylation pathway is highly mutated in bladder transitional cell carcinoma. Furthermore, cancers exhibit distinct evolutionary trajectories of immune escape. Pancreatic adenocarcinoma acquires late mutations in amino acid metabolism, esophageal adenocarcinoma shows early mutations in neuroactive ligand−receptor interaction and IFNγ signaling, and breast adenocarcinoma has late mutations in protein methylation. These findings systematically map the genetic evolution of immune escape across cancer types and lay the groundwork for novel approaches in early detection, immunoprevention, and therapeutic intervention. Citation Format: Wenjie Chen, Toby Baker, Zhihui Zhang, Huw Alexander. Ogilvie, Peter Van Loo, Shengqing Gu. Genetic evolution of immune escape across cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B022.