Abstract A084: Dynamics of tumor immune environment across organs in early and late-stage metastatic pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal five-year survival rate of 13%. Most patients present with metastatic disease, and 80% undergoing surgery relapse within two years. Research on PDAC has traditionally focused on primary tumors, thus most treatment derives from primary tumor biology. Recent evidence unveiled significant differences in the tumor immune microenvironment (TIME) between primary and metastatic lesions. Understanding these differences is crucial, as immunotherapies are predominantly administered to patients with refractory metastatic PDAC, yet traditional treatment fails to account for organ specificity and patient TIME signatures. In this study, we wanted to know why the same cancer cell type in different organs would create different microenvironments in the pancreas, liver, and lungs. To do this, we investigated the TIME in early and late-stage metastatic cohorts by multiplex immunohistochemistry (mIHC), transcriptomic assays and spatial analysis. To profile the TIME of different immune and stromal cells, we employed spatial protein expression using mIHC platform for the early cohort. In total, we applied a 30-plex panel to 56 samples. Our analysis revealed a higher density of COL1A1+ fibroblasts and CD163+ macrophages in the liver compared to other sites. Additionally, liver metastases exhibited significantly fewer CD8+ T cells compared to other organs within the tumor core. These results confirmed the earlier studies regarding the TIME of metastatic lesions, while also showing more macrophage and fibrosis in the liver. In the late-stage cohort, similar trends of decreased immune cell presence and exclusion phenotypes were observed using mIHC and Visium platforms. To explore the underlying mechanisms, we performed transcriptomic assays on the immune compartment. Our findings indicated an enrichment of interferon-positive macrophage subsets, particularly in liver metastases compared to primary PDAC. Additionally, we observed a higher presence of exhaustive CD8+ T cells and regulatory T cells in primary sites compared to liver and lung metastases, suggesting that both primary PDAC and liver metastases possess an immunosuppressive environment. Furthermore, spatial proximity analysis demonstrated that CD8+ T cells were closer to tumor cells in lung metastases compared to liver and primary tumors, reinforcing the notion that lung metastases are more immune-active. Pathway analysis revealed downregulation of antigen presentation and lymphocyte proliferation signaling in liver T cells compared to those in the lungs. Notably, immune infiltration was observed in some liver samples, but the percentage was significantly lower compared to lung samples. This divergence in TIME modulation between organs suggests a significant impact on disease progression in PDAC patients. The significant difference in immuno-response across organ shows why it is critical to consider distinct immune landscapes of different organs and patient histories when developing tailored therapies for advanced PDAC patients. Citation Format: Yu-Lan Kao, Olivia M. Dres, Blake G. Sells, Varun Shenoy, Xiang Li, Kapur Dhami, Paul M. Grandgenett, Li Ding, Liang-I Kang, David G. DeNardo. Dynamics of tumor immune environment across organs in early and late-stage metastatic 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(18_Suppl_3):Abstract nr A084.