Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

作者：Carolina J. García García, Yanqing Huang, Natividad R. Fuentes, Madeleine Turner, Maria E. Monberg, Daniel Lin, Nicholas D. Nguyen, Tara N. Fujimoto, Jun Zhao, Jaewon J. Lee, Vincent Bernard, Meifang Yu, Abagail Delahoussaye, Iancarlos Jiménez Sacarello, Emily G. Caggiano, J. Phan, Amit Deorukhkar, Jessica M. Molkentine, Dieter Saur, Anirban Maitra, Cullen M. Taniguchi · 发表于：Gastroenterology · 年份：2022 · DOI：10.1053/j.gastro.2022.02.024 · 被引用次数：160 · 研究领域：Cancer, Hypoxia, and Metabolism、Immune cells in cancer、Cancer Cells and Metastasis

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. METHODS: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. RESULTS: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 i...