Jackson et al. showed that expression of the pleiotropic Meteorin-like (METRNL) cytokine was higher in CD8+ TILs from multiple cancer types than in patient-matched PBMCs, and higher in pre-exhausted and exhausted than naive murine and human TILs. Repeated TCR stimulation induced CD8+ T cell secretion of METRNL, which boosted the E2F-PPARδ pathway and induced mitochondrial depolarization, ROS accumulation and a compensatory glycolytic shift, DNA damage, apoptosis, and hypofunction of CD8+ T cells. METRNL KO or siRNA knockdown improved CD8+ T cell fitness, activity, and viability, and slowed tumor growth in several mouse models.
Contributed by Paula Hochman
ABSTRACT: Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.
Author Info: (1) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: cjacks53@jhmi.edu. (2) Bloomberg-Kimmel Institute for Immun
Author Info: (1) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: cjacks53@jhmi.edu. (2) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (5) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (7) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (9) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (10) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (13) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (14) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (16) Biomedical Engineering Department, Johns Hopkins University, Baltimore, MD, USA. (17) Biomedical Engineering Department, Johns Hopkins University, Baltimore, MD, USA. (18) Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. (19) Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (20) Center for Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA. (21) Center for Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA. (22) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (23) Biomedical Engineering Department, Johns Hopkins University, Baltimore, MD, USA. (24) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (25) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. (26) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (27) Center for Cell Therapy, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford School of Medicine, Stanford, CA, USA. (28) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (29) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (30) Bloomberg-Kimmel Institute for Immunotherapy, Departments of Oncology and Medicine, and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (31) Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA. Electronic address: mklim@stanford.edu.
