PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma PMID: 37723306

ADC Targets in Oncology

2026-04-10

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

Nat Cancer. 2023 Sep 18. doi: 10.1038/s43018-023-00635-7.

Tim Wartewig ^# ¹ ² ³ , Jay Daniels ^# ⁴ ⁵ , Miriam Schulz ^# ¹ ² , Erik Hameister ¹ ² , Abhinav Joshi ¹ ² , Joonhee Park ⁴ ⁵ , Emma Morrish ¹ ² ⁶ , Anuroop V Venkatasubramani ⁷ , Filippo M Cernilogar ⁸ , Frits H A van Heijster ⁹ , Christian Hundshammer ⁹ , Heike Schneider ² , Filippos Konstantinidis ¹ ² , Judith V Gabler ¹ ² , Christine Klement ¹⁰ , Henry Kurniawan ¹¹ ¹² , Calvin Law ⁴ ⁵ , Yujin Lee ⁴ ⁵ , Sara Choi ⁴ ⁵ , Joan Guitart ⁵ , Ignasi Forne ⁷ , Jérôme Giustinani ¹³ , Markus Müschen ³ ¹⁴ , Salvia Jain ¹⁵ , David M Weinstock ¹⁵ ¹⁶ , Roland Rad ¹⁰ ¹⁷ , Nicolas Ortonne ¹³ ¹⁸ , Franz Schilling ⁹ , Gunnar Schotta ⁸ , Axel Imhof ⁷ , Dirk Brenner ¹¹ ¹² ¹⁹ , Jaehyuk Choi ²⁰ ²¹ ²² ²³ ²⁴ ²⁵ , Jürgen Ruland ²⁶ ²⁷ ²⁸ ²⁹

Affiliations

1. TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany.
2. Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.
3. Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT, USA.
4. Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
5. Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
6. German Cancer Consortium (DKTK), Heidelberg, Germany.
7. Protein Analysis Unit, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany.
8. Department of Molecular Biology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Martinsried, Germany.
9. Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany.
10. Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany.
11. Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
12. Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.
13. Institut Mondor de Recherche Biomédicale, Inserm U955, Paris-Est Créteil University, Créteil, France.
14. Department of Immunobiology, Yale University, New Haven, CT, USA.
15. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
16. Merck Research Laboratories, Boston, MA, USA.
17. Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany.
18. Pathology Department, AP-HP Inserm U955, Henri Mondor Hospital, Créteil, France.
19. Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
20. Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. [email protected].
21. Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. [email protected].
22. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. [email protected].
23. Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. [email protected].
24. Center for Human Immunobiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. [email protected].
25. Center for Synthetic Biology, Northwestern University, Evanston, IL, USA. [email protected].
26. TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany. [email protected].
27. Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany. [email protected].
28. German Cancer Consortium (DKTK), Heidelberg, Germany. [email protected].
29. German Center for Infection Research (DZIF), partner site Munich, Munich, Germany. [email protected].
# Contributed equally.

Abstract

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.