Hypoxia-inducible factor-1α inhibition augments efficacy of programmed cell death 1 antibody in murine prostatic cancer models

This study was designed to explore whether hypoxia-inducible factor-1 alpha (HIF-1 alpha) inhibitor could enhance immunotherapy efficacy in prostate cancer. Western blot was used to detect the expression of HIF-1 alpha 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-1 alpha 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-1 alpha inhibitor IDF-11774. Protein expression of HIF-1 alpha, 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-1 alpha 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-1 alpha 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-1 alpha. HIF-1 alpha inhibitor reduced CD45(+)CD11b(+)Gr-1(+) myeloid-derived suppressor cells (P = 0.0027) and CD45(+) CD11b(+)F4/80(+)CD206(hi) 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-1 alpha inhibition augmented the antitumor efficacy of immune checkpoint inhibitor PD-1 antibody in murine prostate cancer models, probably through modulating the immunosuppressive microenvironment.