Genetic and Pharmaceutical Targeting of HIF-1α Enhances PD-L1 Expression in Normal Tissue while Repressing It in Cancer: An Optimal Strategy for Combination Immunotherapy
Open AccessIn terms of therapeutic efficacy, the superiority of anti-CTLA-4 + anti-PD-1/PD-L1 combination therapy over monotherapy in curative options for many cancer patients is well-documented. However, dual-immune checkpoint blockade is severely limited by high incidence of immune-related adverse events (irAE), which can result in discontinuation of immunotherapy and even death. This is predicated by the fact that the current strategies indiscriminately target CTLA-4 and PD-1/PD-L1 pathways in normal as well cancerous tissues and that the pathways play pivotal roles in guarding the host tissues against immune destruction while allowing cancer cells to evade host immunity. A major challenge for cancer immunotherapy is to eliminate irAE without compromising the synergistic cancer immunotherapeutic effect of dual-immune checkpoint blockade. pharmaceutical or genetic targeting of hypoxia-inducible factor 1α (HIF-1α) suppressed PD-L1 expression on tumor cells and tumor-infiltrated myeloid cells, but unexpectedly induced PD-L1 in normal tissues by enhancing T cell production of IFNγ. Targeting an HIF-1α-PD-L1 axis in tumor cells inflamed the tumor microenvironment (TME), reactivated tumor infiltrated lymphocytes (TILs), and restricted tumor growth in a manner dependent on adaptive immunity. Moreover, liposomal echinomycin potentiated cancer immunotherapeutic effects of CTLA-4 blockade with efficacy comparable to anti-PD-1 antibodies. Importantly, by stimulating an IFNγ-PD-L1 axis in normal tissues, liposomal echinomycin reduced anti-CTLA-4-mediated T cell inflammation in irAE target organs of tumor-bearing mice, and conferred protection from Ipilimumab-induced gastrointestinal (GI)-irAEs in a humanized CTLA4 knockin model. Taken together, the data suggest that dual-targeting of CTLA-4 and HIF-1α may represent a safer and equally effective alternative to current combination therapy with anti-CTLA-4 + anti-PD-1/PD-L1 antibodies.
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