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

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The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function. Immunity Jackson, C. M., Pant, A., Dinalankara, W., Choi, J., Jain, A., Nitta, R., Yazigi, E., Saleh, L., Zhao, L., Nirschl, T. R., Kochel, C. M., Hwa-Lin Bergsneider, B., Routkevitch, D., Patel, K., Cho, K. B., Tzeng, S., Neshat, S. Y., Kim, Y. H., Smith, B. J., Ramello, M. C., Sotillo, E., Wang, X., Green, J. J., Bettegowda, C., Li, G., Brem, H., Mackall, C. L., Pardoll, D. M., Drake, C. G., Marchionni, L., Lim, M. 2024

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 (PPARd) 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-PPARd pathway to support bioenergetic fitness of CD8+ TILs.

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