Abstract A034: KRAS Mutation-Specific effects on the Tumor Immune Microenvironment Drive Tumor Progression

Abstract The immune microenvironment plays a critical role in cancer development, progression and resistance to therapy. KRAS mutations are near-ubiquitous in pancreatic ductal adenocarcinoma (PDAC) and several studies have demonstrated that KRASG12D can create an immunosuppressive tumor microenvironment. However, the immune effects of other oncogenic KRAS variants, such as KRASG12R (representing 20% of PDAC cases) are unknown. Given that specific KRAS mutants display distinct molecular phenotypes, we examined the immune cell composition of KRASG12R pancreatic tumors. Orthotopically implanted mouse tumors derived from KrasG12R/+;Trp53KO pancreatic organoids have a distinct immune profile in comparison to KrasG12D/+;Trp53KO tumors, characterized by an influx of intratumoral CD4+ T cells and mature dendritic cells. 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 human PDAC cohorts revealed enrichment of genes in inflammatory pathways in KRASG12R tumors. Collectively, these data link KRASG12R to a unique immune landscape that is distinct from KRASG12D tumors. Citation Format: Andrew wenger, Tal Baron, Erika Hissong, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Rohit Chandwani, Lukas Dow, Despina Siolas. KRAS Mutation-Specific effects on the Tumor Immune Microenvironment Drive Tumor Progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A034.