Given an association between decreased serum spermidine (SPD) levels and age-related dysfunction, including immune dysfunction, Al-Habsi, Chamoto, Matsumoto, and Nomura et al. explored the impact of SPD T cell effectiveness and metabolism. SPD supplementation in aged mice, and also in young mice, improved the effectiveness of anti-PD-L1 therapy across multiple tumors and genetic backgrounds, enhancing fatty acid oxidation and mitochondrial function in CD8+ T cells. The effects of SPD on mitochondria were rapid (1 hour) and related to allosteric binding and activation of both subunits of mitochondrial trifunctional protein, a key metabolic regulator, and were opposed by spermine.
Contributed by Ed Fritsch
ABSTRACT: Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and β subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.
Author Info: (1) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. National Genetic Ce
Author Info: (1) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. National Genetic Center, Ministry of Health, Muscat, Oman. Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (2) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (3) Department of Developmental Neurobiology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan. (4) Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (5) Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan. (6) Department of Biochemistry, Keio University, Tokyo, Japan. (7) Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan. (8) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (9) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (10) YCI Laboratory for Next-Generation Proteomics, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan. Chemical Biology Mass Spectrometry Platform, Faculty of Science, University of Geneva, Geneva, Switzerland. (11) Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (12) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (13) Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (14) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (15) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (16) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (17) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (18) Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (19) Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (20) Department of Developmental Neurobiology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan. (21) Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan. (22) Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
