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

IF 25.5 1区 医学 Q1 IMMUNOLOGY Immunity Pub Date : 2024-08-06 DOI:10.1016/j.immuni.2024.07.003
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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.

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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
肿瘤浸润淋巴细胞(TIL)功能低下是晚期癌症进展的一个因素,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在很大程度上是未知的。在这里,我们发现肿瘤微环境(TME)中的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 由 CD8+ T 细胞在反复刺激过程中分泌,通过自分泌和旁分泌信号发挥作用。从机制上讲,METRNL增加了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的消减或下调改善了CD8+ T细胞的代谢能力,增强了几种肿瘤模型的肿瘤控制能力,证明了靶向METRNL-E2F-PPARδ途径支持CD8+ TILs生物能的转化潜力。
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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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