Abstract LB-284: Engineering a hypermutant mouse model of NSCLC to modulate immune response

Immune checkpoint inhibitors are an exciting new class of cancer therapy with unprecedented response rates, and have shed light on the importance of understanding the immune context of tumors. Despite achieving durable clinical responses for a subset of patients, immune checkpoint therapies produce variable response rates, even within tumor type, suggesting a need for improved understanding of the tumor-immune cell axis. Recent clinical trials using checkpoint blockade against CTLA-4 and PD-1 have underscored the relevance of tumor mutational landscapes in predicting these response rates. For example, non-small cell lung cancer (NSCLC) patients with high mutational burden and PD-L1 expression respond better to anti-PD-1 treatment than those with high PD-L1 expression alone. While genetically engineered mouse models (GEMMs) of cancer are powerful platforms for testing new therapies, existing models fail to recapitulate the mutational burden and signatures of human cancers, limiting their ability to model relevant immune responses. We have therefore used CRISPR-Cas9 to knockout the DNA mismatch repair (MMR) gene Msh2 in the widely-used Kras and P53 mutant (KP) GEMM of NSCLC. Specifically, lentivirus expressing a short guide RNA (sgRNA) targeting Msh2, and Cre-recombinase, is delivered intra-tracheally into KP mice carrying a Cas9 allele. Whole-exome sequencing reveals elevated mutational burdens in Msh2^KO tumors, as compared to non-targeted controls, and mutational signatures characteristic of MMR deficient human tumors. Histological characterization indicates elevated T cell infiltration of Msh2^KO tumors at early time points, while tumors at later stages show minimal infiltration and appear like immune “cold” human tumors. Our future efforts will test checkpoint blockade therapies combined with immunogenic chemotherapy to facilitate neo-antigen presentation in late stage tumors. Development and characterization of this “hypermutant” model should prove valuable for future preclinical development of immunotherapies in NSCLC.

Citation Format: Olivia C. Smith, Peter M. Westcott, David A. Canner, William M. Rideout, Arjun Bhutkar, Mary C. Beytagh, Tuomas Tammela, Tyler E. Jacks. Engineering a hypermutant mouse model of NSCLC to modulate immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-284.