Abstract A081: Dissecting the Tumor–Immune Landscape of PDAC Liver Metastases to Identify Candidate Drivers of Immune Evasion and Metastatic Outgrowth

Abstract Liver metastases represent a leading cause of mortality in pancreatic ductal adenocarcinoma (PDAC). Recent clinical evidence has revealed distinct immune ecosystems in the liver tumor microenvironment, yet mechanistic insight into the cellular and molecular mechanisms driving those diverse immune landscapes remains unclear. Here we report, computational cellular signaling analysis of single-cell RNA sequencing data from matched primary and liver metastatic samples isolated at early and late time points from the spontaneous genetically engineered mouse model KPC (Pdx1Cre; KrasLSL-G12D; Tp53LSL-R172H). This analysis uncovered several immunomodulatory axes between cancer cells-T cells and cancer cells- macrophages. Validation of these findings were performed using primary tumor cell lines, isolated from the same or littermate tumors as the scRNA-seq dataset. Bulk RNA-seq analysis of these cell lines showed a retention of cancer-derived ligands in culture. In vivo validation using the hemisplenic liver metastatic transplant model confirmed that cell lines isolated from primary tumors, which metastasized spontaneously to the liver, retained liver metastatic outgrowth potential. Flow cytometry and multiplex cytokine profiling of isolated cell lines, non-involved liver, and liver tumors revealed distinct immune population shifts within the metastatic niche and confirmed cancer cell derived immunomodulatory cytokines. This study highlights the interplay between cancer-intrinsic signaling and the immune landscape in PDAC liver metastases and supports future mechanistic exploration. Citation Format: Ayushi Mandloi, Jace Baines, Meet Patel, Christina R. Larson, Robert S. Welner, Julienne L. Carstens. Dissecting the Tumor–Immune Landscape of PDAC Liver Metastases to Identify Candidate Drivers of Immune Evasion and Metastatic Outgrowth [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(18_Suppl_3):Abstract nr A081.