Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses.

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Bargiela, David 
Cunha, Pedro P 
Veliça, Pedro 
Foskolou, Iosifina P  ORCID logo
Barbieri, Laura 

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.


Funder: Knut och Alice Wallenbergs Stiftelse

Funder: Vetenskapsrådet

Funder: Barncancerfonden

Funder: Cancerfonden

CD8+ lymphocytes, hypoxia, immunotherapy, metabolism, vitamin B6, Aminooxyacetic Acid, Animals, CD8-Positive T-Lymphocytes, Hypoxia-Inducible Factor 1, alpha Subunit, Melanoma, Mice, Mice, Inbred C57BL, Neoplasms, Phosphoprotein Phosphatases, Proteomics, Pyridoxal Phosphate, Vitamin B 6
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Front Immunol
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Frontiers Media SA
Wellcome Trust (211143/Z/18/Z)