| First Author | Garcia Garcia CJ | Year | 2022 |
| Journal | Gastroenterology | Volume | 162 |
| Issue | 7 | Pages | 2018-2031 |
| PubMed ID | 35216965 | Mgi Jnum | J:350085 |
| Mgi Id | MGI:7661250 | Doi | 10.1053/j.gastro.2022.02.024 |
| Citation | Garcia Garcia CJ, et al. (2022) Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment. Gastroenterology 162(7):2018-2031 |
| abstractText | 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 Hif1alpha or Hif2alpha in alpha-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2alpha 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 Hif2alpha, but not Hif1alpha, 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 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease. |
