Abstract P023: Mismatch Repair Deficiency is Not Sufficient to Increase Tumor Immunogenicity

Abstract Deficient DNA mismatch repair (dMMR) in human cancer is associated with high tumor mutation burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of these tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of dMMR have helped solidify the importance of TMB in immune response, critical questions remain regarding the role of immune surveillance in the evolution of dMMR tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, dMMR in these models did not result in increased immunogenicity or response to ICB, which we showed is driven by profound intratumoral heterogeneity. Studies in animals depleted of T cells further demonstrated that immune surveillance in dMMR tumors has no impact on TMB but shapes the clonal architecture of neoantigens. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB. Citation Format: Peter M. K. Westcott, Francesc M. Remolar, Olivia Smith, Haley Hauck, Nathan J. Sacks, Zackery A. Ely, Alex M. Jaeger, William M. Rideout, Arjun Bhutkar, Daniel Zhang, Mary C. Beytagh, Roderick T. Bronson, David A. Canner, Santiago Naranjo, Abbey Jin, J. J. Patten, Amanda M. Cruz, Isidro Cortes-Ciriano, Tyler Jacks. Mismatch repair deficiency is not sufficient to increase tumor immunogenicity [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P023.