Dvorakova et al. showed that deletion of prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3 from tumor antigen-specific activated/differentiated CD8+ T cells stabilized hypoxia- inducible factor (HIF)-1α, which is known to regulate T cell function and metabolism; increased HIF-1α-dependent T cell activation, effector functions, and glucose metabolism; and improved the antitumor activity of adoptively transferred T cells in several mouse tumor models, including the immunosuppressive hypoxic TiRP autochthonous inducible melanoma model. In vitro, pharmacologic PHD2 inhibition stabilized HIF-1α in and boosted the effector functions of activated human CD8+ T cells.
Contributed by Paula Hochman
ABSTRACT: While adoptive cell therapy has shown success in hematological malignancies, its potential against solid tumors is hindered by an immunosuppressive tumor microenvironment (TME). In recent years, members of the hypoxia-inducible factor (HIF) family have gained recognition as important regulators of T-cell metabolism and function. The role of HIF signalling in activated CD8 T cell function in the context of adoptive cell transfer, however, has not been explored in full depth. Here we utilize CRISPR-Cas9 technology to delete prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3, thereby stabilizing HIF-1 signalling, in CD8 T cells that have already undergone differentiation and activation, modelling the T cell phenotype utilized in clinical settings. We observe a significant boost in T-cell activation and effector functions following PHD2/3 deletion, which is dependent on HIF-1α, and is accompanied by an increased glycolytic flux. This improvement in CD8 T cell performance translates into an enhancement in tumor response to adoptive T cell therapy in mice, across various tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. These findings hold promise for advancing CD8 T-cell based therapies and overcoming the immune suppression barriers within challenging tumor microenvironments.
Author Info: (1) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. WEL Research Institute, Wavre, 1300, Belgium. (2) de D
Author Info: (1) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. WEL Research Institute, Wavre, 1300, Belgium. (2) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. WEL Research Institute, Wavre, 1300, Belgium. (3) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. WEL Research Institute, Wavre, 1300, Belgium. (4) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. (5) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. WEL Research Institute, Wavre, 1300, Belgium. (6) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. jingjng.zhu@uclouvain.be. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. jingjng.zhu@uclouvain.be. WEL Research Institute, Wavre, 1300, Belgium. jingjng.zhu@uclouvain.be. (7) de Duve Institute, UCLouvain, Brussels, B-1200, Belgium. benoit.vandeneynde@uclouvain.be. Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium. benoit.vandeneynde@uclouvain.be. WEL Research Institute, Wavre, 1300, Belgium. benoit.vandeneynde@uclouvain.be. Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford Oxford, Oxfordshire, UK. benoit.vandeneynde@uclouvain.be.
