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

Abstract

// Tiansuo Zhao 1,* , He Ren 1,* , Li Jia 2 , Jing Chen 1 , Wen Xin 1 , Fan Yan 1 , Jing Li 1 , Xiuchao Wang 1 , Song Gao 1 , Dong Qian 1 , Chongbiao Huang 1 and Jihui Hao 1 1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China 2 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK * These authors contributed equally to this work Correspondence: Jihui Hao, email: // Keywords : Pancreatic ductal adenocarcinoma (PDAC), Immunogenic cell death (ICD), PX-478, Gemcitabine (Gem) Received : October 01, 2014 Accepted : December 09, 2014 Published : December 10, 2014 Abstract Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all the malignancies. Now, gemcitabine (Gem) is the first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem is usually ineffective to the PDAC because of high degree of drug resistance. Hypoxia and immune suppressive milieu are the best-described hallmarks of PDAC; therefore, we investigated the impact of hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with Gem on the induction of immunogenic cell death (ICD). We verified that combined treatment with Gem/PX-478 significantly enhanced the anti-tumor effect and increased proportion of tumor infiltrating T-lymphocytes in Panc02-bearing immune-competent but not in immune-deficient mice. Vaccination using Panc02 cell line treated with single agent or in combination showed significant anti-tumor effects. Pancreatic cell lines treated with Gem and PX-478 can induce an increase in eIF2α phosphorylation was correlated with down-regulation of HIF-1α and elicited exposure of CRT and release of HMGB1 and ATP. Only co-treated cells induced DC maturation/phagocytosis and IFN-γ secretion by cytotoxic T lymphocytes. Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization. We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.