Abstract A037: Oncogenic KRAS signaling reversibly suppresses immunotherapy responses in non-small cell lung cancer

KRAS is a major oncogenic driver in lung cancer and is altered in roughly one quarter of adult cancers. Beyond its well-established roles in growth signaling and survival, KRAS is increasingly recognized as a regulator of tumor immunogenicity. Prior studies describe a KRAS-associated “immune cold” phenotype marked by lower interferon signaling, reduced antigen presentation, and broader changes in tumor–immune interactions. Although direct KRAS inhibition was considered unfeasible for decades, recent breakthroughs have enabled mutation-specific targeting with G12C inhibitors such as sotorasib and adagrasib, along with newer RAS-ON inhibitors that block active RAS independent of mutational status. To test how KRAS modulation shapes T cell-associated immune responses, we utilized an in vitro model of T-cell mediated immune lung cancer cell killing in the presence and absence of KRAS inhibition. Specifically, we utilized DSG2-specific chimeric antigen receptor T cells (CAR T cells) to model immunotherapy targeting desmoglein-2 (DSG2) positive KRASG12C NSCLC cells (NCI-H1792) co-treated with the KRASG12C inhibitor sotorasib. CD19 CAR T cells were used as a negative control for these CD19-negative cells. Immunotherapy-associated cell death was quantified using real-time impedance measurements (xCELLigence) and metabolic activity using a resazurin-based viability assay (Alamar Blue). We also measured immune activity by release of interferon-gamma (IFN-γ) cytokine release in co-culture. First, we validated the cytotoxicity of the DSG2-directed CAR T cells against H1792 cells at various effector:target ratios. Next, we performed a dose response of enhanced cytotoxicity with combinatorial sotorasib and DSG2 CAR T cells. These experiments revealed an IC50 of approximately 0.03 μM for sotorasib in that context. Treatment with DSG2-CAR T, but not CD19 CAR T, was associated with increased IFN-γ production. Notably, KRAS inhibition did not change DSG2 surface expression, suggesting that effects on immune function arise from downstream signaling and cell-dependent factors rather than altered antigen availability. Taken together, these findings suggest that oncogenic KRAS impairs T cell-mediated immunotherapy (i.e. CAR T or immune checkpoint inhibitors) responses in a cell-dependent manner, and furthermore provides provocative rationale for translational approaches combining KRAS inhibition (both sotorasib and RAS-ON approaches) to improve immunotherapy responses in NSCLC. Citation Format: Drithi Patel, Md Nazmul Huda, Jasmine Alvarez, Ramkrishna Mitra, Miao Cao, Andrea Feci, Robert Carlson, Adam Snook, Erik Blomain. Oncogenic KRAS signaling reversibly suppresses immunotherapy responses in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A037.