Combination therapy of HIF1α 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 anti‐tumor 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 and purified T cells 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 inhibitors with HIF1α inhibitors 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 anti‐tumor immunity by combining HIF1α and Tregs inhibitors.

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