Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells.

Autor: Dvorakova T; de Duve Institute, UCLouvain, Brussels, B-1200, Belgium.; Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium.; WEL Research Institute, Wavre, 1300, Belgium., Finisguerra V; de Duve Institute, UCLouvain, Brussels, B-1200, Belgium.; Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium.; WEL Research Institute, Wavre, 1300, Belgium., Formenti M; de Duve Institute, UCLouvain, Brussels, B-1200, Belgium.; Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium.; WEL Research Institute, Wavre, 1300, Belgium., Loriot A; de Duve Institute, UCLouvain, Brussels, B-1200, Belgium., Boudhan L; de Duve Institute, UCLouvain, Brussels, B-1200, Belgium.; Ludwig Institute for Cancer Research, Brussels, B-1200, Belgium.; WEL Research Institute, Wavre, 1300, Belgium., Zhu J; 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., Van den Eynde BJ; 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.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 06; Vol. 15 (1), pp. 7789. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1038/s41467-024-51782-z
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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