Abstract 3966: Divergent immune responses in pancreatic cancer driven by KRAS mutations

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted KrasG12R/+;Trp53KO mouse pancreatic tumors have a distinct immune profile in comparison to KrasG12D/+;Trp53KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available and real-world human PDAC datasets an enrichment of dendritic cells and other immune related cell pathways in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to an unique immunogenic role. Citation Format: Andrew Wenger, Katherine Bacchi, Huanhuan Sun, Adrian Vega, Whitney Sisso, Erika Hissong, Lukas Dow, Despina Siolas. Divergent immune responses in pancreatic cancer driven by KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3966.