| First Author | Jackson CM | Year | 2024 |
| Journal | Immunity | Volume | 57 |
| Issue | 8 | Pages | 1864-1877.e9 |
| PubMed ID | 39111315 | Mgi Jnum | J:353386 |
| Mgi Id | MGI:7710805 | Doi | 10.1016/j.immuni.2024.07.003 |
| Citation | Jackson CM, et al. (2024) The cytokine Meteorin-like inhibits anti-tumor CD8(+) T cell responses by disrupting mitochondrial function. Immunity 57(8):1864-1877.e9 |
| abstractText | 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 (PPARdelta) 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-PPARdelta pathway to support bioenergetic fitness of CD8(+) TILs. |
