Coenzyme A fuels T cell anti-tumor immunity.

Autor:	St Paul M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Saibil SD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Han S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Israni-Winger K; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Lien SC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Laister RC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Sayad A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Penny S; National Research Council, Human Health Therapeutics, Halifax, NS B3H 3Z1, Canada., Amaria RN; Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA., Haydu LE; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA., Garcia-Batres CR; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Kates M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Mulder DT; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Robert-Tissot C; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Gold MJ; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Tran CW; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada., Elford AR; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Nguyen LT; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Pugh TJ; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Pinto DM; National Research Council, Human Health Therapeutics, Halifax, NS B3H 3Z1, Canada., Wargo JA; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA., Ohashi PS; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1C1, Canada. Electronic address: pohashi@uhnresearch.ca.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2021 Dec 07; Vol. 33 (12), pp. 2415-2427.e6.
DOI:	10.1016/j.cmet.2021.11.010
Abstrakt:	Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8 + T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8 + Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity. Competing Interests: Declaration of interests M.S.P., S.D.S., and P.S.O. have filed for a patent pertaining to this work. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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