Combination therapy of HIFα inhibitors and Treg depletion strengthen the anti-tumor immunity in mice

Abstract

Hypoxia-inducible factor 1 alpha (HIF1α), under hypoxic conditions, is known to play an oxygen sensor stabilizing role by exerting context- and cell-dependent stimulatory and inhibitory functions in immune cells. Nevertheless, how HIF1α regulates T cell differentiation and functions in tumor settings has not been elucidated. Herein, we demonstrated that T-cell-specific deletion of HIF1α improves the inflammatory potential and memory phenotype of CD8⁺ T cells. We validated that T cell-specific HIF1α ablation reduced the B16 melanomas development with the indication of ameliorated antitumor immune response with enhanced IFN-γ⁺ CD8⁺ T cells despite the increase in the Foxp3⁺ regulatory T-cell population. This was further verified by treating tumor-bearing mice with a HIF1α inhibitor. Results indicated that HIF1α inhibitor also recapitulates HIF1α ablation effects by declining tumor growth and enhancing the memory and inflammatory potential of CD8⁺ T cells. Furthermore, a combination of Treg inhibitor with HIF1α inhibitor can substantially reduce tumor size. Collectively, these findings highlight the notable roles of HIF1α in distinct CD8⁺ T-cell subsets. This study suggests the significant implications for enhancing the potential of T cell-based antitumor immunity by combining HIF1α and Tregs inhibitors.

Keywords: CD8+ T cells; Foxp3; Hypoxia-inducible factor 1 (HIF1α); Regulatory T cells; Tumor immunity.