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

Autor: Gnanaprakasam JNR; 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., Kushwaha B; 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., Liu L; 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., Chen X; 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., Kang S; 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., Wang T; 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., Cassel TA; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Adams CM; Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA., Higashi RM; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Scott DA; Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Xin G; Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA., Li Z; Department of Microbial Infection and Immunity, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA., Yang J; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA., Lane AN; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Fan TW; Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Zhang J; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA., Wang R; 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.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2023 Aug; Vol. 5 (8), pp. 1423-1439. Date of Electronic Publication: 2023 Aug 07.
DOI: 10.1038/s42255-023-00856-1
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: