PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.

Autor: Wartewig T; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.; Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA., Daniels J; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Schulz M; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany., Hameister E; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany., Joshi A; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany., Park J; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Morrish E; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Venkatasubramani AV; Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., Cernilogar FM; Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., van Heijster FHA; Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany., Hundshammer C; Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany., Schneider H; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany., Konstantinidis F; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany., Gabler JV; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany., Klement C; Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany., Kurniawan H; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Law C; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Lee Y; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Choi S; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Guitart J; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Forne I; Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., Giustinani J; Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France., Müschen M; Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA.; Department of Immunobiology, Yale University, New Haven, CT, USA., Jain S; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Weinstock DM; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Merck Research Laboratories, Boston, MA, USA., Rad R; Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany.; Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany., Ortonne N; Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France.; Pathology Department, AP-HP Inserm U955, Henri Mondor Hospital, Créteil, France., Schilling F; Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany., Schotta G; Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., Imhof A; Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., Brenner D; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark., Choi J; Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Center for Human Immunobiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Center for Synthetic Biology, Northwestern University, Evanston, IL, USA. jaehyuk.choi@northwestern.edu., Ruland J; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany. j.ruland@tum.de.; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany. j.ruland@tum.de.; German Cancer Consortium (DKTK), Heidelberg, Germany. j.ruland@tum.de.; German Center for Infection Research (DZIF), partner site Munich, Munich, Germany. j.ruland@tum.de.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2023 Oct; Vol. 4 (10), pp. 1508-1525. Date of Electronic Publication: 2023 Sep 18.
DOI: 10.1038/s43018-023-00635-7
Abstrakt: The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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