Liu et al. reported that CD40-mediated signaling boosted fatty acid oxidation (FAO) and glutamine metabolism to promote epigenetic reprogramming of macrophages towards pro-inflammatory/anti-tumorigenic polarization. CD40 activation triggered glutamine-to-lactate conversion and fine-tuned the NAD+/NADH ratio to sustain FAO. FAO generated acetyl-CoA and increased histone acetylation at promoters and enhancers of pro-inflammatory marker genes. Genetic ablation of Ldha (encoding lactate dehydrogenase) and Gls (encoding glutaminase 1) impaired anti-CD40 monoclonal antibody-induced antitumor responses and re-education of tumor-associated macrophages.
Contributed by Shishir Pant
ABSTRACT: Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD(+)/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.
Author Info: (1) Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. pusteliu@nhri.edu.tw. (2) Institute of Cellular and System Medicine, National Hea
Author Info: (1) Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. pusteliu@nhri.edu.tw. (2) Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. (3) Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. Ludwig Lausanne Branch, Lausanne, Switzerland. (4) Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. Ludwig Lausanne Branch, Lausanne, Switzerland. (5) Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. Ludwig Lausanne Branch, Lausanne, Switzerland. (6) Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. (7) Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. (8) School of Life Science, Shaoxing University, Shaoxing, People's Republic of China. (9) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (10) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (11) Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. (12) Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. ping-chih.ho@unil.ch. Ludwig Lausanne Branch, Lausanne, Switzerland. ping-chih.ho@unil.ch.
