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

Author

Listed:
  • Tereza Dvorakova

    (UCLouvain
    Ludwig Institute for Cancer Research
    WEL Research Institute)

  • Veronica Finisguerra

    (UCLouvain
    Ludwig Institute for Cancer Research
    WEL Research Institute)

  • Matteo Formenti

    (UCLouvain
    Ludwig Institute for Cancer Research
    WEL Research Institute)

  • Axelle Loriot

    (UCLouvain)

  • Loubna Boudhan

    (UCLouvain
    Ludwig Institute for Cancer Research
    WEL Research Institute)

  • Jingjing Zhu

    (UCLouvain
    Ludwig Institute for Cancer Research
    WEL Research Institute)

  • Benoit J. Van den Eynde

    (UCLouvain
    Ludwig Institute for Cancer Research
    WEL Research Institute
    University of Oxford Oxford)

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.

Suggested Citation

  • Tereza Dvorakova & Veronica Finisguerra & Matteo Formenti & Axelle Loriot & Loubna Boudhan & Jingjing Zhu & Benoit J. Van den Eynde, 2024. "Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51782-z
    DOI: 10.1038/s41467-024-51782-z
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