美国斯坦福大学医学院Michael Lim和约翰霍普金斯大学医学院Christopher M. Jackson研究组合作的论文发现，细胞因子Meteorin-like通过破坏线粒体功能抑制抗肿瘤CD8+ T细胞反应。该研究于2024年8月6日发表于国际学术期刊《免疫》杂志。

研究人员发现肿瘤微环境（TME）中免疫细胞分泌的代谢活性细胞因子Meteorin-like (METRNL) 会诱导CD8⁺ T细胞的生物能衰竭。METRNL是CD8⁺ T细胞在受到反复刺激时分泌的，通过自分泌和旁分泌信号发挥功能。

从机制上讲，METRNL增强了E2F-过氧化物酶体增殖激活受体δ（PPARδ）的活性，导致线粒体去极化和氧化磷酸化降低，从而引发生物能代偿性地转向糖酵解。METRNL缺失或下调改善了CD8⁺ T细胞的代谢能力，增强了几种肿瘤模型中的肿瘤控制能力，证明靶向METRNL-E2F-PPARδ途径可改变CD8⁺ TILs生物能的转化。

据了解，肿瘤浸润淋巴细胞（TIL）功能低下是晚期癌症进展的一个诱因，也是免疫疗法的一个常见靶点。新的证据表明，在强刺激过程中，新陈代谢不足会导致T细胞功能低下，但在这种情况下启动新陈代谢重编程的信号通路是未知的。

附：英文原文

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

Author: Christopher M. Jackson, Ayush Pant, Wikum Dinalankara, John Choi, Aanchal Jain, Ryan Nitta, Eli Yazigi, Laura Saleh, Liang Zhao, Thomas R. Nirschl, Christina M. Kochel, Brandon Hwa-Lin Bergsneider, Denis Routkevitch, Kisha Patel, Kwang Bog Cho, Stephany Tzeng, Sarah Y. Neshat, Young-Hoon Kim, Barbara J. Smith, Maria Cecilia Ramello, Elena Sotillo, Xinnan Wang, Jordan J. Green, Chetan Bettegowda, Gordon Li, Henry Brem, Crystal L. Mackall, Drew M. Pardoll, Charles G. Drake, Luigi Marchionni, Michael Lim

Issue&Volume: 2024-08-06

Abstract: Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression ofadvanced cancers and is a frequent target of immunotherapy. Emerging evidence indicatesthat metabolic insufficiency drives T cell hypofunction during tonic stimulation,but the signals that initiate metabolic reprogramming in this context are largelyunknown. 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 translationalpotential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitnessof CD8+ TILs.

DOI: 10.1016/j.immuni.2024.07.003

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00352-2