Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response

J. N.Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A. Cassel, Christopher M. Adams, Richard M. Higashi, David A. Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N. Lane, Teresa W.M. Fan, Ji Zhang, Ruoning Wang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.

Original languageEnglish
Pages (from-to)1423-1439
Number of pages17
JournalNature Metabolism
Volume5
Issue number8
DOIs
StatePublished - Aug 2023

Bibliographical note

Funding Information:
We thank X. Song, N. Restifo and W. Terence for their reagents and advice. This work was supported by 1UO1CA232488-01, 2R01AI114581-06, R01CA247941 and 1R01AI175004-01 from the National Institutes of Health (NIH); V2014-001 from the V Foundation; and 128436-RSG-15-180-01-LIB from the American Cancer Society (to R.W.); as well as the T32 Ruth L. Kirschstein National Research Service Award CA269052 from the NIH (to S.K.). The Sanford Burnham Prebys (SBP) Cancer Metabolism Core was supported by the SBP National Cancer Institute (NCI) Cancer Center Support Grant P30 CA030199 (to D.A.S.). The Center for Environmental and Systems Biochemistry Core was partly supported by the Markey Cancer Center support grant P30CA177558 (to T.W.-M.F.).

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

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

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