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

Hypoxia-inducible factor 1 alpha (HIF1a), 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 HIF1a regulates T cell differentiation and functions in tumor settings has not been elucidated. Herein, we demonstrated that T-cell-specific deletion of HIF1a improves the inflammatory potential and memory phenotype of CD8(+) T cells. We validated that T cell-specific HIF1a ablation reduced the B16 melanomas development with the indication of ameliorated antitumor immune response with enhanced IFN-?(+) CD8(+) T cells despite the increase in the Foxp3(+) regulatory T-cell population. This was further verified by treating tumor-bearing mice with a HIF1a inhibitor. Results indicated that HIF1a inhibitor also recapitulates HIF1a ablation effects by declining tumor growth and enhancing the memory and inflammatory potential of CD8(+) T cells. Furthermore, a combination of Treg inhibitor with HIF1a inhibitor can substantially reduce tumor size. Collectively, these findings highlight the notable roles of HIF1a in distinct CD8(+) T-cell subsets. This study suggests the significant implications for enhancing the potential of T cell-based antitumor immunity by combining HIF1a and Tregs inhibitors.