Blockade of 6-phosphogluconate dehydrogenase generates CD8+ effector T cells with enhanced anti-tumor function
Saeed Daneshmandi,
Teresa Cassel,
Penghui Lin,
Richard M. Higashi,
Gerburg M. Wulf,
Vassiliki A. Boussiotis,
Teresa W.-M. Fan,
Pankaj Seth
Affiliations
Saeed Daneshmandi
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Teresa Cassel
Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY 40536, USA
Penghui Lin
Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY 40536, USA
Richard M. Higashi
Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
Gerburg M. Wulf
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Vassiliki A. Boussiotis
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Teresa W.-M. Fan
Center for Environmental and Systems Biochemistry, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Corresponding author
Pankaj Seth
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Corresponding author
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.
