Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.
Cunha, Pedro P
Johnson, Randall S
Frontiers in immunology
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Bargiela, D., Cunha, P. P., Veliça, P., Foskolou, I. P., Barbieri, L., Rundqvist, H., & Johnson, R. S. (2022). Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.. Frontiers in immunology, 13 https://doi.org/10.3389/fimmu.2022.837669
Funder: Knut och Alice Wallenbergs Stiftelse
Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses <i>in vitro</i> and <i>in vivo</i>. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5'-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation <i>in vitro</i> and <i>in vivo</i>. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.
Metabolism, Hypoxia, Immunotherapy, Vitamin B6, Cd8+ Lymphocytes
Wellcome Trust (211143/Z/18/Z)
External DOI: https://doi.org/10.3389/fimmu.2022.837669
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335854
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/