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PHD2 constrains the anti-tumor CD8+ T cell activity

ABSTRACT: The PHD/HIF pathway has been implicated in a wide range of immune and inflammatory processes, including in the oxygen‐deprived tumor microenvironment. To examine the effect of HIF stabilization in anti‐tumor immunity, we deleted Phd2 selectively in T lymphocytes using the cre/lox system. We show that the deletion of PHD2 in lymphocytes resulted in enhanced regression of EG7‐OVA tumors, in a HIF‐1adependent manner. The enhanced control of neoplastic growth correlated with increased poly‐functionality of CD8+ tumor‐infiltrating lymphocytes, i.e. enhanced expression of IFN‐g, TNF‐a and granzyme B. Phenotypic and transcriptomic analyses point to a key role of glycolysis in sustaining CTL activity in the tumor bed and identifies the PHD2/HIF‐1 pathway as potential target for intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE216536 | GEO | 2022/12/01

REPOSITORIES: GEO

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Project description:The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing an effector/Th1-like phenotype. Concomitantly, the expression of innate-type cytokines such as IL1-β, IL-12p40, IL-12p35 and TNF-α was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs do not efficiently control inflammatory response in vivo, in particular immune responses characterized by IFN-γ production. Further analysis revealed that Treg dysregulation is largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs revealed an altered expression of several chemokine receptors including CXCR3, a finding corroborated by the altered in vivo localization of PHD2-deficient Tregs in splenic tissues. Collectively, these findings uncover an important role of the PHD2-HIF2α axis in regulatory T cell positioning and trafficking.

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PHD2 constrains the anti-tumor CD8+ T cell activity

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