TY - JOUR
T1 - PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma
AU - Wartewig, Tim
AU - Daniels, Jay
AU - Schulz, Miriam
AU - Hameister, Erik
AU - Joshi, Abhinav
AU - Park, Joonhee
AU - Morrish, Emma
AU - Venkatasubramani, Anuroop V.
AU - Cernilogar, Filippo M.
AU - van Heijster, Frits H.A.
AU - Hundshammer, Christian
AU - Schneider, Heike
AU - Konstantinidis, Filippos
AU - Gabler, Judith V.
AU - Klement, Christine
AU - Kurniawan, Henry
AU - Law, Calvin
AU - Lee, Yujin
AU - Choi, Sara
AU - Guitart, Joan
AU - Forne, Ignasi
AU - Giustinani, Jérôme
AU - Müschen, Markus
AU - Jain, Salvia
AU - Weinstock, David M.
AU - Rad, Roland
AU - Ortonne, Nicolas
AU - Schilling, Franz
AU - Schotta, Gunnar
AU - Imhof, Axel
AU - Brenner, Dirk
AU - Choi, Jaehyuk
AU - Ruland, Jürgen
N1 - Funding Information:
We thank K. Burmeister, A. Doddajjappanavar, V. Höfl, N. Prause, M. Arens, K. Pechloff, W. Lee, Z. Kurgyis, P. Gaulard and A. Wahida for providing excellent technical assistance or helpful discussions and the Core Facility Cell Analysis at TranslaTUM at Klinikum rechts der Isar of the Technical University Munich for their support. We also acknowledge core facilities at Northwestern including the flow cytometry core and the Skin Biology and Disease Resource Center. This work was supported by research grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (project ID 210592381, SFB 1054; project ID 360372040, SFB 1335; project ID 395357507, SFB 1371; project ID 369799452, TRR 237; project ID 452881907, TRR 338, RU 695/9-1, RU 695/12-1), The Leukemia & Lymphoma Society and the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme awarded grant agreement 834154 to J.R. and grant agreement 820374 to F.S. F.S. was further supported by the DFG (project ID 68647618, SFB 824). J.C. was supported by the National Institutes of Health (1DP2AI136599-01), the American Cancer Society (Research Scholar Grant RSG-20-050-01), the Bakewell Foundation and the Leukemia Lymphoma Society Scholar Award (1377-21). T.W. was supported by the Cancer Research Institute (CRI4029) and is currently funded by NIH–NCI (1K99CA277586-01). J.D. was supported by NIH–NCI grants F30 CA265107 and T32 CA009560.Work in G.S.’s laboratory was funded by the DFG (project ID 213249687, SFB 1064 TP3; project ID 329628492, SFB 1321 TP13). D.B. was supported by FNR CORE grants (C21/BM/15796788 and C18/BM/12691266). M.M. was supported by research grants from the National Institutes of Health (R35CA197628, R01CA157644, R01CA213138 and P01CA233412) and the Howard Hughes Medical Institute (HHMI-55108547). Work in the laboratory of A.I. was funded by research grants from the DFG (project ID 325871075-SFB1309) and the Bundesministerium für Bildung und Forschung (FKZ, FKZ161L0214F, ClinspectM).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85171327868
UR - https://pubmed.ncbi.nlm.nih.gov/37723306
U2 - 10.1038/s43018-023-00635-7
DO - 10.1038/s43018-023-00635-7
M3 - Article
C2 - 37723306
SN - 2662-1347
VL - 4
SP - 1508
EP - 1525
JO - Nature Cancer
JF - Nature Cancer
IS - 10
ER -