Nature cancer · 2023
PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Wartewig Tim, Daniels Jay, Schulz Miriam, Hameister Erik, Joshi Abhinav, Park Joonhee, Morrish Emma, Venkatasubramani Anuroop V, Cernilogar Filippo M, van Heijster Frits H A, Hundshammer Christian, Schneider Heike, Konstantinidis Filippos, Gabler Judith V, Klement Christine, Kurniawan Henry, Law Calvin, Lee Yujin, Choi Sara, Guitart Joan, Forne Ignasi, Giustinani Jérôme, Müschen Markus, Jain Salvia, Weinstock David M, Rad Roland, Ortonne Nicolas, Schilling Franz, Schotta Gunnar, Imhof Axel, Brenner Dirk, Choi Jaehyuk, Ruland Jürgen
Аннотация
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.