The cytokine Meteorin-like inhibits anti-tumor CD8 + T cell responses by disrupting mitochondrial function.

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.
Competing Interests: Declaration of interests C.M.J. is a consultant for Egret Therapeutics with equity interests in the company. He is an inventor on a patent filed by Johns Hopkins University for using immune checkpoint agonists to treat cerebrovascular disorders. He receives research support from Biohaven, InCephalo, and Grifols. Johns Hopkins University has filed a provisional patent on METRNL blockade for cancer treatment on which C.M.J., M.L., A.P., H.B., and J.C. are inventors. E.S. consults for Lepton Pharmaceuticals and Galaria and consults for and holds equity in Lyell Immunopharma. C.B. is a consultant for Depuy-Synthes and Bionaut Labs. C.L.M. has multiple patents in the field of CAR T cell therapy; is an equity holder, director, and consultant for Syncopation Life Sciences and Link Cell Therapies; and is an equity holder and consultant for Lyell Immunopharma, Mammoth Biosciences, Ensoma Therapeutics, and Apricity Bio. She also consults for Immatics, Glaxo Smith Kline, and Bristol Myers Squibb. H.B. is a consultant for Perosphere, AsclepiX Therapeutics, StemGen, Accelerating Combination Therapies, Catalio Nexus Fund II. LLC, LikeMinds, Inc. Acuity Bio Corp, InSightec, Galen Robotics, and Nurami Medical. M.L. has received research support from Arbor, BMS, Accuray, Tocagen, Biohaven, Kyrin-Kyowa, and Biohaven; has been a consultant to Tocagen, VBI, InCephalo Therapeutics, Pyramid Bio, Merck, BMS, Insightec, Biohaven, Sanianoia, Hemispherian, Black Diamond Therapeutics, and Novocure; is a shareholder of Egret Therapeutics; and has patents for focused radiation + checkpoint inhibitors, local chemotherapy + checkpoint inhibitors, and checkpoint agonists for neuro-inflammation.
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