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

Abstract

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.

A Systematic Review on the Impact of Hypofractionated and Stereotactic Radiotherapy on Immune Cell Subpopulations in Cancer Patients

“…While a number of studies found that CFRT generates an increased level of both Treg and MDSC cells, expanding and promoting T cell dysfunction towards immunosuppression, it seems that HF schemes are more advantageous in stimulating the immune system [ 29 ]. Considering the effect on TME, in murine models, the comparison of CFRT with HFRT revealed that the latter fractionation schedule may inhibit hypoxia and reduce the recruitment of immunosuppressive cells into primary tumors, generating a microenvironment with lower PD-L1 levels and boosting not only local, but also systemic CD8- mediated anticancer immunity [ 30 ]; although, a large number of studies showed that high-dose/fraction irradiation may alter tumor blood vessels, increasing tumor hypoxia with the recruitment of immunosuppressive cells into tumors and a PDL-1 increase [ 31 , 32 ].…”

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

“…A bulk of studies have validated that metformin also promotes the cancer-killing functions of CD8 + T cells in metabolic regulation-dependent manners ( Pearce et al, 2009 ; Chen et al, 2021b ; Chao et al, 2022 ). Metformin treatment downregulates immune checkpoint expression and glycolytic cancer flux in a HIF-1α inhibition-dependent manner, thereby improving ICB therapy ( Chung et al, 2021 ; Song et al, 2022b ). Furthermore, the metabolic rewiring effects-mediated by metformin can affect the metabolic interaction between cancer cells and non-malignant cells within TME.…”

Liposomal Drug Delivery Systems for Cancer Therapy: The Rotterdam Experience

“…Understanding tumor immunology has revealed mechanisms and factors involved in the escape of cancer cells from immune surveillance and showed how cancer cells harness immune responses in favor of their proliferation. Exploring the role of factors such as immune checkpoints and immunosuppressive cytokines, as well as the downregulation of immune stimulatory biomolecules, along with the emergence of chronic inflammation that results in immune dysfunction and interferences with the intrinsic activity of the host immune cells, provides opportunities to help the immune system to attack malignant cells [ 162 , 163 ]. Nanocarriers, especially liposomes, have been exploited in immunotherapy, either as carriers or adjuvants in cancer vaccines [ 164 ], or for selective delivery of immunomodultory agents [ 165 , 166 , 167 ].…”