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.
Highlights
Immunotherapy is an established treatment for cancer and targeting immune cell metabolism has emerged as a promising immunotherapeutic strategy [1, 2]
Vitamin B6 is obtained from dietary sources and is converted to an active form, pyridoxal 5’-phosphate (PLP), by the action of pyridoxal kinase (PDXK) and pyridoxamine 5’-phosphate oxidases (PNPO)
At 12 hours following activation, there was an increase in gene expression of positive regulators of PLP levels (PDXP, PNPO) relative to naïve cells, whereas there was no change in gene expression of the negative regulator of PLP levels (PDXP)
Summary
Immunotherapy is an established treatment for cancer and targeting immune cell metabolism has emerged as a promising immunotherapeutic strategy [1, 2]. Metabolic programs directly influence cell function and modulation of these programs has been shown to redirect T cell proliferation and differentiation. Metabolic control of T cell activity can be harnessed for therapeutic purposes by augmenting or suppressing immune responses in vivo. The identification of effective metabolic targets that confer cell-specific and durable immunomodulatory responses remains an ongoing priority. In T cells, the hypoxia-inducible factor (HIF) transcription factors are master regulator of metabolic genes that direct cell fate and function [3–7]. Metabolite availability, along with activation signals downstream of the T cell receptor (TCR) and co-stimulatory receptors, dynamically
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