{Reference Type}: Journal Article
{Title}: The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
{Author}: Jackson CM;Pant A;Dinalankara W;Choi J;Jain A;Nitta R;Yazigi E;Saleh L;Zhao L;Nirschl TR;Kochel CM;Hwa-Lin Bergsneider B;Routkevitch D;Patel K;Cho KB;Tzeng S;Neshat SY;Kim YH;Smith BJ;Ramello MC;Sotillo E;Wang X;Green JJ;Bettegowda C;Li G;Brem H;Mackall CL;Pardoll DM;Drake CG;Marchionni L;Lim M;
{Journal}: Immunity
{Volume}: 57
{Issue}: 8
{Year}: 2024 Aug 13
{Factor}: 43.474
{DOI}: 10.1016/j.immuni.2024.07.003
{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.