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

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     «

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; Scho...     »

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.      «

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 gl...     »