Yuan, Hu, and Ju et al. showed that in vitro blockade of the ion channel N-methyl-D-aspartate receptor (NMDAR) polarized macrophages toward an M1-like phenotype. NMDAR antagonist treatment of mice bearing fibrosarcoma or liver tumors decreased immunosuppression by TAMs, boosted TIL effector function, inhibited tumor growth, and prolonged host survival. scRNAseq showed NMDAR regulated Ca++ influx, ROS production, and mitochondrial function in macrophages, and decreased immunosuppression by TAMs to promote T and NK cell antitumor activity. NMDAR antagonism improved anti-PD-1 antibody efficacy against liver tumors established in mice.
Contributed by Paula Hochman
ABSTRACT: Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking NMDAR functionally and metabolically altered TAM phenotypes, such that they could better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to the elimination of the majority of established preclinical liver tumors. Thus, our study uncovered an unknown role for NMDAR in regulating macrophages in the TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for tumor immunotherapy.
Author Info: (1) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical Un
Author Info: (1) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (2) Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Department of Genetics, Xuzhou Engineering Research Center of Medical Genetics and Transformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (3) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (4) St. Anna Children's Cancer Research Institute, Medical University of Vienna, Vienna 1210, Austria. (5) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (6) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (7) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (8) Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (9) Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China. (10) Department of Pulmonary Medicine, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China. (11) Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China. Department of Biochemistry and Molecular Biology, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China. (12) Department of Research and Development, OriCell Therapeutics Co. Ltd, Shanghai 200131, China. (13) Translational Oncology Discovery Group, QIMR Berghofer Medical Research Institute, Brisbane 4702, Australia. (14) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (15) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (16) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (17) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. (18) Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
