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

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.

Baohuoside I inhibits resistance to cisplatin in ovarian cancer cells by suppressing autophagy via downregulating HIF‐1α/ATG5 axis

“…Hypoxic regulates the expression of HIF-1α, a critical mediator in tumor progression. 25 Stabilization of HIF-1α through extracellular regulated kinase signaling has been linked to the promotion of platinum-resistance in ovarian cancer. 26 The upregulation of HIF-1α has been shown to promote chemotherapy resistance of ovarian cancer cells.…”

Hypoxia inducible factor-1ɑ as a potential therapeutic target for osteosarcoma metastasis

“…Treatment with PD-1 inhibitors in OS mice model results in a significant reduction in the probability of lung metastasis ( Zheng et al, 2018 ). Although the role of HIF-1α on PD-1/PD-L1 in OS cells remains unconfirmed, inhibiting the expression of HIF-1α can effectively reduce the expression level of PD-1 in glioma and prostate cancer cells ( Ding et al, 2021 ; Shen et al, 2022 ). Decreased expression of HIF-1α and PD-L1 promotes the infiltration of CD8 T cells, and increases the levels of TNF-α, IFN-γ, thereby significantly enhancing the efficacy of anti-PD-1 therapy in gastric cancer cells ( Wang Z. et al, 2023b ).…”

Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance

“…Inhibition of ENTPD2 by ARL67156 and POM-1 reduces tumor growth and improves the effectiveness of immune checkpoint inhibitors of programmed death-1 (PD-1) (clone RMP1-14) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) (clone 9D9), implying that ENTPD2 is a prospective cancer treatment target [ 111 ]. Similarly, the HIF-1α inhibitor IDF-11774 was found to enhance the efficacy of anti-PD-1 treatment in murine prostate cancer xenograft models [ 106 ]. Further analysis revealed that the combination of IDF-11774 with an anti-PD-1 antibody reduced the presence of immunosuppressive cells such as M2 macrophages and myeloid-derived suppressor cells, while increasing the number of effector T cells in the tumor microenvironment [ 106 ].…”