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

Authors

J. N. Rashida Gnanaprakasam, Nationwide Children’s Hospital
Bhavana Kushwaha, Nationwide Children’s Hospital
Lingling Liu, Nationwide Children’s Hospital
Xuyong Chen, Nationwide Children’s Hospital
Siwen Kang, Nationwide Children’s Hospital
Tingting Wang, Nationwide Children’s Hospital
Teresa A. Cassel, University of KentuckyFollow
Christopher M. Adams, Mayo Clinic
Richard M. Higashi, University of KentuckyFollow
David A. Scott, Sanford Burnham Prebys Medical Discovery Institute
Gang Xin, The Ohio State University
Zihai Li, The Ohio State University
Jun Yang, St. Jude Children’s Research Hospital; The University of Tennessee Health Science Center
Andrew N. Lane, University of KentuckyFollow
Teresa Whei-Mei Fan, University of KentuckyFollow
Ji Zhang, Indiana University School of Medicine
Ruoning Wang, Nationwide Children’s HospitalFollow

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.

Document Type

Article

Publication Date

8-2023

Notes/Citation Information

© The Author(s) 2023

Digital Object Identifier (DOI)

https://doi.org/10.1038/s42255-023-00856-1

Funding Information

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.).

Repository Citation

Gnanaprakasam, J. N. Rashida; Kushwaha, Bhavana; Liu, Lingling; Chen, Xuyong; Kang, Siwen; Wang, Tingting; Cassel, Teresa A.; Adams, Christopher M.; Higashi, Richard M.; Scott, David A.; Xin, Gang; Li, Zihai; Yang, Jun; Lane, Andrew N.; Fan, Teresa Whei-Mei; Zhang, Ji; and Wang, Ruoning, "Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response" (2023). Markey Cancer Center Faculty Publications. 299.
https://uknowledge.uky.edu/markey_facpub/299