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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy characterized by poor response to existing therapeutic options. This resistance to treatment is partly due to its extensive inflammatory, desmoplastic stromal response, along with a hypoxic microenvironment. Although tumor hypoxia induces adaptive responses in both cancer cells and the surrounding stroma, most studies on the role of hypoxia in tumorigenesis have focused on cancer cell-intrinsic properties. The impact of hypoxia on stromal cells themselves and their interactions with cancer cells has remained largely unknown. We previously showed that inflammatory cancer-associated fibroblasts (iCAFs), which express high levels of cytokines and chemokines, are preferentially located in hypoxic regions of PDAC, and that hypoxia promotes an inflammatory fibroblast phenotype. The iCAF phenotype has been correlated with highly immunosuppressive features of PDAC. These findings and our preliminary observation that CD8+ T cells are largely excluded from hypoxic PDAC regions, raise the possibility that hypoxia suppresses the infiltration and activation of CD8+ T cells by modulating their interactions with inflammatory fibroblasts. By culturing CD8+ T cells under hypoxia with conditioned media from co-cultures of pancreatic cancer cells and fibroblasts, we have found that cancer cells and fibroblasts decrease CD8+ T cell proliferation and cytotoxic activity under low oxygen conditions. We are working to elucidate the mechanism by which hypoxia regulates CD8+ T cell infiltration and activation through cancer cell-fibroblast crosstalk. Citation Format: Ashley M. Mello, Tenzin Ngodup, Katelyn L. Donahue, Marina Pasca Di Magliano, Kyoung Eun Lee. The role of hypoxia in CD8+ T cell localization and function in pancreatic cancer 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 Suppl₂): Abstract nr A036.
Mello et al. (Sun,) studied this question.