Hypoxia-inducible factor-1α inhibition augments efficacy of programmed cell death 1 antibody in murine prostatic cancer models
Zhonghua Shen, Qiong Pei, Huimin Zhang, Chao Yang, Haijun Cui, Bin Li, Jian Liu, Zhiqiang Bo, Feng Wei, Min Zhang, Chuang Liu
Abstract
This study was designed to explore whether hypoxia-inducible factor-1α (HIF-1α) inhibitor could enhance immunotherapy efficacy in prostate cancer. Western blot was used to detect the expression of HIF-1α in the tumor and peritumor tissues from prostate cancer patients. The analysis from Cancer Genome Atlas database was used to show an association between HIF-1α expression and survival rate in prostate cancer patients. Murine prostate cell-derived xenograft (CDX) model was set up in both nude mice and BALB/c mice to observe the therapeutic effect of HIF-1α inhibitor IDF-11774. Protein expression of HIF-1α, as well as changes in the immune microenvironment, was detected. Moreover, the synergistic antitumor effect of IDF-11774 and PD-1 antibody was detected in another murine prostate cancer model. HIF-1α was found to have higher expression in prostate cancer tumor tissue than in peritumor tissue, and the expression level was negatively correlated with survival rate (P = 0.0157). HIF-1α inhibitor IDF-11774 reduced tumor volume and exhibited better efficacy in BALB/c mouse model (P < 0.0001) with normal immune system, with the same suppression level against HIF-1α. HIF-1α inhibitor reduced CD45+CD11b+Gr-1+ myeloid-derived suppressor cells (P = 0.0027) and CD45+ CD11b+F4/80+CD206hi M2 macrophages (P = 0.0059) but increased the abundance of CD45+CD3+CD8+ T cells (P = 0.0002) and CD45+CD3+CD4+ T cells (P = 0.0001) in tumor-infiltrating immune cells. The same synergistic effect was observed in RM-1 murine prostate CDX tumor model. HIF-1α inhibition augmented the antitumor efficacy of immune checkpoint inhibitor PD-1 antibody in murine prostate cancer models, probably through modulating the immunosuppressive microenvironment.