PHD2 Constrains Antitumor CD8+ T-cell Activity

• Published in: Cancer immunology research 2023-03, Vol.11 (3), p.339-350
• Main Authors: Bisilliat Donnet, Charlotte, Acolty, Valérie, Azouz, Abdulkader, Taquin, Anaëlle, Henin, Coralie, Trusso Cafarello, Sarah, Denanglaire, Sébastien, Mazzone, Massimiliano, Oldenhove, Guillaume, Leo, Oberdan, Goriely, Stanislas, Moser, Muriel
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases; Neoplasms; Oxygen; Procollagen-Proline Dioxygenase - metabolism; Tumor Microenvironment
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-22-0099

The prolyl hydroxylase domain/hypoxia-inducible factor (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 antitumor 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-1α-dependent manner. The enhanced control of neoplastic growth correlated with increased polyfunctionality of CD8+ tumor-infiltrating lymphocytes, as indicated by enhanced expression of IFNγ, TNFα, and granzyme B. Phenotypic and transcriptomic analyses pointed to a key role of glycolysis in sustaining CTL activity in the tumor bed and identified the PHD2/HIF-1 pathway as a potential target for cancer immunotherapy.