Abstract B114: Distinct Oncogenic KRAS Mutations Shape Tumor Immunity in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is generally considered an immune-suppressive malignancy, yet the tumor-intrinsic programs that determine its immune microenvironment remain incompletely defined. KRAS mutations are a known driver of pancreatic cancer, occuring in over 90% of tumors. Historically, all oncogenic KRAS mutations were assumed to be biologically equivalent. However, emerging clinical and molecular data suggest otherwise: KRASG12R tumors, which represent approximately 20% of PDACs, are associated with the most favorable clinical outcomes, while KRASG12D tumors are associated with the worst outcomes, suggesting the presence of biologically distinct tumor subtypes. To understand the basis of the clinical observation, we analyzed human RNA-sequencing datasets from more than 600 patients and found significant enrichment of immune-related pathways in KRASG12R PDAC compared with KRASG12D PDAC. To mechanistically investigate this observation, we generated mutation-defined PDAC organoid models expressing either KRASG12R or KRASG12D. Although the models proliferated similarly in vitro, orthotopic implantation into immunocompetent mice demonstrated that KRASG12R tumors grew more slowly and exhibited an immune-active tumor microenvironment. Mechanistically, KRASG12R tumors exhibited enhanced antigen-presentation programs, suggesting that KRAS mutation status identity may regulate tumor immunogenicity. Spatial single-cell profiling of human PDAC specimens confirmed these findings, revealing enrichment of antigen-presenting cells and immune activation markers in KRASG12R tumors. Our data identify oncogenic KRAS mutation subtype as a determinant of immune microenvironment in PDAC and provide a rationale for mutation-informed therapeutic strategies