Abstract A038: The hypoxic regulation of macrophage function in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is marked by an extensive fibroinflammatory stroma and a low-oxygen (hypoxic) microenvironment, which contribute to disease progression and therapeutic resistance. Within the PDAC stroma, macrophages and cancer-associated fibroblasts (CAFs) are the predominant cell types. Macrophages are a major immunosuppressive population in PDAC. These cells are highly plastic and, as a result, their environment plays an important role in regulating their function. Macrophages adapt to hypoxia primarily by stabilizing hypoxia-inducible factors (HIFs), which are oxygen-labile transcription factors. Although PDAC is profoundly hypoxic and both the tumor cells and stromal cells experience hypoxia, the effects of hypoxia and HIFs on macrophages and their interactions with other stromal cells in PDAC are not yet fully understood. We found that hypoxia promotes the acquisition of inflammatory cancer-associated fibroblasts (inflammatory CAFs), a fibroblast subtype that produces high levels of cytokines and chemokines. Utilizing a hypoxia marker in mouse models of PDAC, we have observed that inflammatory CAFs and macrophages are predominantly situated in hypoxic tumor regions compared with normoxic regions, while T cells are largely absent from these oxygen-poor regions. These preliminary data raise the possibility that inflammatory fibroblasts induced by hypoxia promote macrophage infiltration into hypoxic tumor regions and facilitate an immunosuppressive macrophage phenotype. We have also found that when macrophages are exposed to conditioned media derived from fibroblast cultures under either hypoxic or normoxic conditions, factors secreted from the hypoxia-exposed fibroblasts promote an immunosuppressive macrophage phenotype. We are currently identifying the factors released from hypoxic fibroblasts that drive the immunosuppressive macrophage phenotype. Future work will focus on evaluating the effects of macrophage-intrinsic responses to hypoxia through HIFs on pancreatic tumorigenesis in vivo. Citation Format: Sean Hannifin, Ashley M Mello, Tenzin Ngodup, Katelyn L Donahue, Marina Pasca di Magliano, Kyoung Eun Lee. The hypoxic regulation of macrophage 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 Suppl_2):Abstract nr A038.