Abstract LB371: Enhancing anti-tumor immunity with dual inhibition of KRASG12Cand PD-1 in colorectal cancer

Abstract RAS mutations are common oncogenic drivers, occurring in 20% of human cancers, with KRAS mutations present in 40% of colorectal cancer (CRC) cases. These mutations constitutively activate the MAPK pathway, driving tumor progression. Although KRAS-G12C inhibitors have shown success in non-small cell lung cancer, their efficacy in CRC remains limited, with response rates below 20%. Emerging evidence suggests oncogenic KRAS signaling fosters an immunosuppressive tumor microenvironment. Using a syngeneic KRAS-G12C CRC mouse model, we investigated how KRAS inhibition synergizes with immune responses, providing a rationale for combining KRAS inhibitors with immune checkpoint blockade. Our findings demonstrate that combining KRAS-G12C inhibitors with anti-PD1 therapy results in a more pronounced and durable reduction in tumor volume compared to either monotherapy. Notably, KRAS-G12C inhibition significantly enhances CD3+CD8+ T cell infiltration into the tumor microenvironment relative to vehicle-treated controls. Single-cell RNA sequencing further supports these observations, revealing increased infiltration of CD8+ cytotoxic T cells in KRAS-G12C inhibitor-treated tumors, coupled with upregulation of genes associated with interferon gamma production and T cell activation. Importantly, tumor cells exhibited significant downregulation of Ras pathway genes, alongside enrichment of genes related to antigen presentation and the MHC Class I peptide-loading complex. Importantly, scRNA-seq analyses of pre-treatment and on-treatment biopsies from a patient with a KRAS-G12C mutant tumor treated with a KRAS-G12C inhibitor and the PD-1 antibody tislelizumab revealed striking similarities to our mouse models. Combination therapy led to a substantial reduction in tumor burden and a notable increase in cytotoxic CD8+ T cell infiltration in on-treatment biopsies. Gene ontology analyses further highlighted an enrichment of pathways associated with heightened tumor immunogenicity driven by interferon regulatory factors, along with a significant increase in the interferon alpha response score. Mechanistically, KRAS-G12C inhibition activated the cGAS-STING pathway in response to cytosolic double-strand DNA accumulation, triggering the production of Type I interferons. These interferons subsequently stimulated the expression of T cell-recruiting interferon-stimulated genes, such as CXCL9 and CXCL10. Together, our findings establish a critical link between KRAS inhibition and enhanced anti-tumor immunity, shedding light on potential mechanisms that underlie therapeutic responses and providing a rationale for novel combination strategies to improve outcomes in KRAS-G12C mutant colorectal cancer. Citation Format: Parasvi S. Patel, Apekshya Panda, Jacquelyn Curtis, Elijah Kushner, Ferran Fece De la Cruz, Alvin Morales-Giron, Caroline Zielinski, Jacy Fang, Tomonori Oka, Jun Tian, Shadmehr Demehri, Nir Hacohen, Rebecca Heist, Scott Kopetz, Moshe Sade-Feldman, Ryan B. Corcoran. Enhancing anti-tumor immunity with dual inhibition of KRASG12Cand PD-1 in colorectal cancer [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 LB371.