HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)

High-dose hypofractionated radiation such as SABR (stereotactic ablative radiotherapy) evokes an anti-tumor immune response by promoting a series of immune-stimulating processes, including the release of tumor-specific antigens from damaged tumor cells and the final effector phase of immune-mediated lysis of target tumor cells. High-dose hypofractionated radiation also causes vascular damage in tumors, thereby increasing tumor hypoxia and upregulation of hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha, the master transcription factors for the cellular response to hypoxia. HIF-1 alpha and HIF-2 alpha are critical factors in the upregulation of immune suppression and are the master regulators of immune evasion of tumors. Consequently, SABR-induced increase in anti-tumor immunity is counterbalanced by the increase in immune suppression mediated by HIF alpha. Inhibition of HIF-1 alpha with small molecules such as metformin downregulates immunosuppressive pathways, including the expression of immune checkpoints, and it improves or restores the anti-tumor immunity stimulated by irradiation. Combinations of HIF alpha inhibitors, particularly HIF-1 alpha inhibitors, with immune checkpoint blocking antibodies may represent a novel approach to boost the overall anti-tumor immune profile in patients and thus enhance outcomes after SABR.

Automated summary

High-dose hypofractionated radiation stimulates anti-tumor immune response but also increases immune suppression mediated by HIF alpha. Inhibition of HIF-1 alpha can restore radiation-induced anti-tumor immunity. Combination of HIF-1 alpha inhibitors with immune checkpoint blocking antibodies may enhance overall anti-tumor immune profile.