Blockade of 6-phosphogluconate dehydrogenase generates CD8+ effector T cells with enhanced anti-tumor function

Cell Reports

Penghui Lin¹  Teresa W.-M. Fan²  Teresa Cassel³  Vassiliki A. Boussiotis⁴  Gerburg M. Wulf⁴  Richard M. Higashi⁴  Pankaj Seth⁵  Saeed Daneshmandi⁵ 

[1] Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA;Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY 40536, USA;Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;

关键词: 6PGD;    pentose phosphate pathway;    effector T cells;    metabolism;    reactive oxygen species;    tumor immunotherapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Although T cell expansion depends on glycolysis, T effector cell differentiation requires signaling via the production of reactive oxygen species (ROS). Because the pentose phosphate pathway (PPP) regulates ROS by generating nicotinamide adenine dinucleotide phosphate (NADPH), we examined how PPP blockade affects T cell differentiation and function. Here, we show that genetic ablation or pharmacologic inhibition of the PPP enzyme 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP results in the generation of superior CD8+ T effector cells. These cells have gene signatures and immunogenic markers of effector phenotype and show potent anti-tumor functions both in vitro and in vivo. In these cells, metabolic reprogramming occurs along with increased mitochondrial ROS and activated antioxidation machinery to balance ROS production against oxidative damage. Our findings reveal a role of 6PGD as a checkpoint for T cell effector differentiation/survival and evidence for 6PGD as an attractive metabolic target to improve tumor immunotherapy.

【 授权许可】

Unknown