Abstract A085: Elucidating the Crosstalk between Cancer Associated Fibroblasts and the T Regulatory/T Helper 2 Axis in Pancreas Cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is a dismal disease with a 5-year survival rate of only 13%. A hallmark feature of this disease is its abundant microenvironment that consists of dense fibrotic stroma and immune cells of suppressive nature that inhibit cytotoxic T cell activity. Our previous work has demonstrated that depletion of Regulatory T cells (Tregs) in a mouse model of PDA unexpectedly accelerates carcinogenesis, without enhancing the anti-tumor immune response. We determined that this paradoxical outcome was driven by a shift in fibroblasts upon Treg depletion, which in turn increased infiltration and polarization of immunosuppressive macrophages. Building on these findings, we sought to study whether direct crosstalk between T cells and fibroblasts was at play in eliciting this immunosuppressive phenotype. Our exploration into the fate of CD4 T cells in Treg-depleted PDA revealed a striking enrichment of T helper 2 (TH2) cells, characterized by elevated production of type II cytokines such as IL-4 and IL-13. Notably, our in vitro studies revealed that type II cytokines directly signal to pancreatic fibroblasts and elicit expression of CCL family cytokines, potentially explaining the increase in macrophage recruitment. In vivo, blockade of IL4 significantly reduced tumor growth in an orthotopic mouse model of PDA, underscoring the therapeutic potential of targeting Th2 signaling. Most importantly, we found that PDA patients with progressive disease exhibit elevated levels of type II cytokines in the plasma compared to those with non-progressive disease, suggesting a strong association between elevated type II cytokines and poor clinical outcomes. Our results provide new insights into the complex cellular crosstalk within PDA microenvironment, revealing a marked rewiring of immune-stromal interaction following Treg depletion. Furthermore, our study suggests potential new therapeutic targets to modulate the immune response and alleviate immunosuppression in PDA. Citation Format: Padma Kadiyala, Chang Xu, Kristee Brown, Carlos Espinoza, Jude Okoye, Megan Procario, Shelby Stakenas, Brian Griffith, Katelyn Donahue, Wenting Du, Nandini Arya, Ahmed Elhossiny, Jacqueline Morales, Xi He, Jiaqi Shi, Timothy Frankel, Filip Bednar, Eileen Carpenter, Yaqing Zhang, Marina Pasca Di Magliano. Elucidating the Crosstalk between Cancer Associated Fibroblasts and the T Regulatory/T Helper 2 Axis in Pancreas 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 A085.