Abstract LB366: KRASG12C inhibition enhances immunogenicity in KRASG12C-mutant colorectal cancer

Abstract RAS mutations are among the most prevalent oncogenic mutations, found in approximately 20% of human cancers. KRAS, the predominantly mutated isoform of RAS, is mutated in 40% of colorectal cancer (CRC) and leads to constitutive activation of the MAPK pathway and other downstream effectors. Despite recent FDA approval for KRASG12C selective inhibitor in non-small cell lung cancer, the response rate in CRC is below 20%, posing a challenge for treatment of these tumors. Several studies have implicated oncogenic KRAS signaling in creating an immunosuppressive tumor microenvironment; therefore, we hypothesized that KRAS inhibitors can enhance anti-tumor immunity, providing a rationale for their combination with immune checkpoint blockade. Using a syngeneic KRASG12C CRC mouse model with knockout of APC, TP53, and SMAD4, we examined tumor cell-intrinsic mechanism of cooperativity between KRAS inhibition and immune response. We found that combining KRASG12C inhibition with anti-PD1 produced a more substantial and sustained reduction in tumor volume compared with KRAS or PD-1 inhibition alone. KRASG12C inhibition led to a significant increase in CD3+CD8+ T cell infiltration compared with vehicle control. Single-cell RNA-sequencing corroborated our observations and revealed increased T cell infiltration in KRASG12C tumors following KRASG12C inhibition. Moreover, these T cells upregulated genes involved in interferon gamma production and T cell activation. Importantly, we observed a significant reduction in the Ras pathway genes, specifically in the tumor cell population, along with enrichment of genes involved in abnormal antigen presentation and MHC Class I peptide loading complex. Mechanistically, we found that KRASG12C inhibition activates the innate immune response, which subsequently induce Type I interferons that activate the expression of T cell-recruiting interferon stimulated genes like CXCL9, CXCL10, IFIT1, IFIT2, and IFIT3. Our data presents a connection between KRAS inhibition and anti-tumor immunity, providing insights into novel combination strategies for KRASG12C colorectal cancers. Citation Format: Parasvi S. Patel, Jun Tian, Ferran Fece de la Cruz, Jacquelyn Curtis, Apekshya Panda, Tomonori Oka, Shadmehr Demehri, Moshe Sade-Feldman, Scott Koptez, Ryan B. Corcoran. KRASG12C inhibition enhances immunogenicity in KRASG12C-mutant colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB366.