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

Abstract

AbstractHypoxia‐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.