PMID- 37550596 OWN - NLM STAT- MEDLINE DCOM- 20230825 LR - 20231011 IS - 2522-5812 (Electronic) IS - 2522-5812 (Linking) VI - 5 IP - 8 DP - 2023 Aug TI - Asparagine restriction enhances CD8(+) T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response. PG - 1423-1439 LID - 10.1038/s42255-023-00856-1 [doi] AB - 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. CI - (c) 2023. The Author(s). FAU - Gnanaprakasam, J N Rashida AU - Gnanaprakasam JNR AUID- ORCID: 0000-0002-9086-0949 AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. FAU - Kushwaha, Bhavana AU - Kushwaha B AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. FAU - Liu, Lingling AU - Liu L AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. FAU - Chen, Xuyong AU - Chen X AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. FAU - Kang, Siwen AU - Kang S AUID- ORCID: 0000-0002-3851-8812 AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. FAU - Wang, Tingting AU - Wang T AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. FAU - Cassel, Teresa A AU - Cassel TA AD - Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA. FAU - Adams, Christopher M AU - Adams CM AD - Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA. FAU - Higashi, Richard M AU - Higashi RM AUID- ORCID: 0000-0002-3256-0622 AD - Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA. FAU - Scott, David A AU - Scott DA AUID- ORCID: 0000-0002-8668-2449 AD - Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. FAU - Xin, Gang AU - Xin G AD - Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA. FAU - Li, Zihai AU - Li Z AUID- ORCID: 0000-0003-4603-927X AD - Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA. FAU - Yang, Jun AU - Yang J AUID- ORCID: 0000-0002-0770-9659 AD - Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA. AD - Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA. FAU - Lane, Andrew N AU - Lane AN AUID- ORCID: 0000-0003-1121-5106 AD - Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA. FAU - Fan, Teresa W-M AU - Fan TW AD - Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA. FAU - Zhang, Ji AU - Zhang J AUID- ORCID: 0000-0002-9274-1767 AD - Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Wang, Ruoning AU - Wang R AUID- ORCID: 0000-0001-9798-8032 AD - Center for Childhood Cancer, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. ruoning.wang@nationwidechildrens.org. LA - eng GR - R01 CA244625/CA/NCI NIH HHS/United States GR - T32 CA269052/CA/NCI NIH HHS/United States GR - R01 AG060637/AG/NIA NIH HHS/United States GR - U01 CA232488/CA/NCI NIH HHS/United States GR - P30 CA030199/CA/NCI NIH HHS/United States GR - P30 CA177558/CA/NCI NIH HHS/United States GR - R01 AI114581/AI/NIAID NIH HHS/United States GR - R01 AR071762/AR/NIAMS NIH HHS/United States GR - R01 AI175004/AI/NIAID NIH HHS/United States GR - R01 CA247941/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230807 PL - Germany TA - Nat Metab JT - Nature metabolism JID - 101736592 RN - 0 (NF-E2-Related Factor 2) RN - 7006-34-0 (Asparagine) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - *CD8-Positive T-Lymphocytes MH - NF-E2-Related Factor 2/genetics/metabolism MH - Asparagine/metabolism MH - Glucose/metabolism MH - *Neoplasms/therapy/metabolism PMC - PMC10447245 COIS- The authors declare no competing interests. EDAT- 2023/08/08 00:42 MHDA- 2023/08/25 06:42 PMCR- 2023/08/07 CRDT- 2023/08/07 23:35 PHST- 2022/09/20 00:00 [received] PHST- 2023/07/05 00:00 [accepted] PHST- 2023/08/25 06:42 [medline] PHST- 2023/08/08 00:42 [pubmed] PHST- 2023/08/07 23:35 [entrez] PHST- 2023/08/07 00:00 [pmc-release] AID - 10.1038/s42255-023-00856-1 [pii] AID - 856 [pii] AID - 10.1038/s42255-023-00856-1 [doi] PST - ppublish SO - Nat Metab. 2023 Aug;5(8):1423-1439. doi: 10.1038/s42255-023-00856-1. Epub 2023 Aug 7.