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

Tim Wartewig, Jay Daniels, Miriam Schulz, Erik Hameister, Abhinav Joshi, Joonhee Park, Emma Morrish, Anuroop V. Venkatasubramani, Filippo M. Cernilogar, Frits H.A. van Heijster, Christian Hundshammer, Heike Schneider, Filippos Konstantinidis, Judith V. Gabler, Christine Klement, Henry Kurniawan, Calvin Law, Yujin Lee, Sara Choi, Joan GuitartIgnasi Forne, Jérôme Giustinani, Markus Müschen, Salvia Jain, David M. Weinstock, Roland Rad, Nicolas Ortonne, Franz Schilling, Gunnar Schotta, Axel Imhof, Dirk Brenner, Jaehyuk Choi*, Jürgen Ruland*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1508-1525
Number of pages18
JournalNature Cancer
Volume4
Issue number10
DOIs
StatePublished - Oct 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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