Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.
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Authors
Bargiela, David
Cunha, Pedro P
Veliça, Pedro
Barbieri, Laura
Rundqvist, Helene
Johnson, Randall S
Publication Date
2022Journal Title
Front Immunol
ISSN
1664-3224
Publisher
Frontiers Media SA
Volume
13
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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.. Front Immunol, 13 https://doi.org/10.3389/fimmu.2022.837669
Description
Funder: Knut och Alice Wallenbergs Stiftelse
Funder: Vetenskapsrådet
Funder: Barncancerfonden
Funder: Cancerfonden
Abstract
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 in vitro and in vivo. 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 in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.
Keywords
Metabolism, Hypoxia, Immunotherapy, Vitamin B6, Cd8+ Lymphocytes
Sponsorship
Wellcome Trust (211143/Z/18/Z)
Identifiers
35251031, PMC8891565
External DOI: https://doi.org/10.3389/fimmu.2022.837669
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335854
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