Hypoxia-activated prodrug and antiangiogenic therapies cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration.

ABSTRACT: We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre-derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and adaptive resistance mechanisms involved in response to 2 established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast with prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy despite qualitative improvements to the CD8+ T cell response. Bulk tum

SUBMITTER: Liu A 

PROVIDER: S-EPMC10906452 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature