Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma

摘要: Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all malignancies. Now, gemcitabine (Gem) first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem usually ineffective to PDAC because of high degree resistance. Hypoxia and immune suppressive milieu are best-described hallmarks PDAC; therefore, we investigated impact hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with on induction immunogenic cell death (ICD). We verified that combined treatment Gem/PX-478 significantly enhanced anti-tumor effect increased proportion tumor infiltrating T-lymphocytes Panc02-bearing immune-competent but not immune-deficient mice. Vaccination using Panc02 treated single agent or showed significant effects. lines PX-478 can induce an increase eIF2α phosphorylation was correlated down-regulation HIF-1α elicited exposure CRT release HMGB1 ATP. Only co-treated cells induced DC maturation/phagocytosis IFN-γ secretion by cytotoxic T lymphocytes. Altogether, inhibition growth immunization. propose elicits Gem-induced response eliminates inducing ICD.