PDF(Pubmed)
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.
摘要：
肿瘤浸润淋巴细胞（TIL）功能减退有助于晚期癌症的进展，并且是免疫疗法的常见靶标。新的证据表明，在强直刺激期间，代谢不足会导致T细胞功能减退，但是在这种情况下启动代谢重编程的信号在很大程度上是未知的。这里,我们发现类似Meteorin（METRNL），肿瘤微环境（TME）中免疫细胞分泌的代谢活性细胞因子，诱导CD8+T细胞的生物能量衰竭。METRNL在重复刺激期间由CD8+T细胞分泌,并且经由自分泌和旁分泌信号传导两者起作用。机械上,METRNL增加E2F-过氧化物酶体增殖物激活受体δ（PPARδ）活性，导致线粒体去极化和减少的氧化磷酸化，这引发了补偿性生物能量向糖酵解的转变。Metrnl消融或下调改善了CD8+T细胞的代谢适应性，并增强了几种肿瘤模型中的肿瘤控制，证明了靶向METRNL-E2F-PPARδ途径以支持CD8TIL的生物能量适应性的翻译潜力。
