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

Abstract

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.

• Authors: Saeed Daneshmandi, Teresa Cassel, Penghui Lin, Richard M Higashi, Gerburg M Wulf, Vassiliki A Boussiotis, Teresa W-M Fan, Pankaj Seth
• Journal: Cell reports (Cell Rep) Vol. 34 Issue 10 Pg. 108831 (03 09 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 33691103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Reactive Oxygen Species
• 6-Aminonicotinamide
• Phosphogluconate Dehydrogenase
• Superoxide Dismutase
• superoxide dismutase 2
• Granzymes

Topics

• 6-Aminonicotinamide (chemistry, pharmacology)
• Animals
• CD8-Positive T-Lymphocytes (cytology, drug effects, immunology, metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Granzymes (genetics, metabolism)
• Humans
• Immunotherapy
• Listeria monocytogenes (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism)
• Neoplasms (metabolism, therapy)
• Pentose Phosphate Pathway (drug effects, physiology)
• Phosphogluconate Dehydrogenase (antagonists & inhibitors, genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Superoxide Dismutase (genetics, metabolism)
• Transplantation, Heterologous