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-1α and HIF-2α, the master transcription factors for the cellular response to hypoxia. HIF-1α and HIF-2α 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 HIFα. Inhibition of HIF-1α 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 HIFα inhibitors, particularly HIF-1α 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.
Bibliographical noteFunding Information:
Funding: University of Minnesota Cancer Center Internal Research fund to C.W.S. and NRF-2020R1A2C2101772 to H.J.P., Winthrop P. Rockefeller Cancer Institute Teams Science Award (R.J.G.)
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
- HIF-1α inhibitor
- HIF-2α inhibitor
- immune checkpoints
- tumor hypoxia
PubMed: MeSH publication types
- Journal Article