The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia

Hypoxia inducible factor-1 alpha (HIF-1 alpha) up-regulates the expression of programmed death ligand-1 (PD-L1) in some extracranial malignancies. However, whether it could increase PD-L1 expression in intracranial tumor is still unknown. Here, we explored the relationship between HIF-1 alpha and PD-L1 expression in glioma, and investigated their clinical significance. In glioma patients, HIF-1 alpha and PD-L1 were overexpressed in high grade glioma tissues and were significantly associated with poor survival. In glioma cells, PD-L1 expression was induced under hypoxia condition, and the enhanced PD-L1 expression was abrogated by either HIF-1 alpha knock-down or HIF-1 alpha inhibitor treatment. Furthermore, ChIP-qPCR analysis showed the direct binding of HIF-1 alpha to PD-L1 proximal promoter region, providing evidence that HIF-1 alpha up-regulates PD-L1 in glioma. In glioma murine model, the combination treatment with HIF-1 alpha inhibitor and anti-PD-L1 antibody caused a more pronounced suppressive effect on tumor growth compared to either monotherapy. Immunologically, the combination treatment improved both dendritic cell (DC) and CD8(+) T cell activation. Overall, our results demonstrated that positive correlation between PD-L1 and HIF-1 alpha in glioma, and provide an alternative strategy, inhibiting HIF-1 alpha, as combination therapies with immunotherapies to advance glioma treatment.

Automated summary

The study showed a positive correlation between PD-L1 and HIF-1α in glioma, with their overexpression associated with poor survival. HIF-1α was found to induce PD-L1 expression under hypoxic conditions, which could be abrogated by inhibiting HIF-1α. Combination therapy of HIF-1α inhibitor and anti-PD-L1 antibody demonstrated enhanced tumor growth suppression and improved immune activation.