Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

Tingting Wang, J. N.Rashida Gnanaprakasam, Xuyong Chen, Siwen Kang, Xuequn Xu, Hua Sun, Lingling Liu, Hayley Rodgers, Ethan Miller, Teresa A. Cassel, Qiushi Sun, Sara Vicente-Muñoz, Marc O. Warmoes, Penghui Lin, Zayda Lizbeth Piedra-Quintero, Mireia Guerau-de-Arellano, Kevin A. Cassady, Song Guo Zheng, Jun Yang, Andrew N. LaneXiaotong Song, Teresa W.M. Fan, Ruoning Wang

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. We demonstrate that the ribose subunit of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors, and that cancer cells display diverse capacities to utilize inosine as a carbon source. Moreover, the supplementation with inosine enhances the anti-tumour efficacy of immune checkpoint blockade and adoptive T-cell transfer in solid tumours that are defective in metabolizing inosine, reflecting the capability of inosine to relieve tumour-imposed metabolic restrictions on T cells.

Original languageEnglish
Pages (from-to)635-647
Number of pages13
JournalNature Metabolism
Volume2
Issue number7
DOIs
StatePublished - Jul 1 2020

Bibliographical note

Funding Information:
This work was supported by 1R21CA227926-01A1 and 1UO1CA232488-01 from the National Institutes of Health (Cancer Moonshot program), 1R01AI114581 from the National Institutes of Health, V2014-001 from the V-Foundation and 128436-RSG-15-180-01-LIB from the American Cancer Society (to R.W.); 130421-RSG-17-071-01-TBG from the American Cancer Society and 1R01CA229739 from the National Cancer Institute (to J.Y.); 1P01CA163223-01A1, 1U24DK097215-01A1 (to T.W.-M.F., A.N.L.); and Redox Metabolism Shared Resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). 13C-enriched standards were obtained from the National Institutes of Health Common Fund Metabolite Standards Synthesis Core (http://www. metabolomicsworkbench.org/standards/index.php). We thank J. Sherman for critically reading and editing the manuscript.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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