Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with limited effective treatment options. While activating mutations in KRAS occur in over 90% of PDAC cases, emerging evidence suggests that distinct KRAS alleles confer distinct biological and clinical phenotypes. Notably, patients with the KRASG12R mutation, present in 18% of PDAC cases, have exhibit significantly improved survival compared to those with the more common KRASG12D mutation, found in 40% of cases. To futher explore this clinical observation, we analyzed human RNA sequencing data from the “Know Your Tumor” program and identified an enrichment of immune-related pathways in KRASG12R tumors compared to KRASG12D tumors. We then developed an orthotopic transplantation mouse model using genetically engineered pancreatic organoids expressing either KRASG12R or KRASG12D mutations to investigate underlying immune related mechanisms. Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors in syngeneic C57/Bl6 mice have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. These findings were also seen in human PDAC samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and in patient resection specimens, which demonstrated enrichment of dendritic cell subtypes in KRASG12R tumors compared to KRASG12D mutant tumors. Functional studies using preclinical models revealed KRASG12R tumor growth was T cell-dependent, whereas KRASG12D tumors were unaffected by loss of T cells. Collectively, these data link the KRASG12R mutation to an unique immunogenic role, that may be susceptible to immune-based therapies. Citation Format: Huanhuan Sun, Katherine Bacchi, Andrew Wenger, Adrian Vega, Whitney Sisso, Kawther Abdilleh, Maria Paz. Zafra, Rohit Chandwani, Lukas Dow, Despina Siolas. KRAS Mutation-Specific Immune Microenvironments in Pancreatic Cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A091.
Sun et al. (2025) studied this question.