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FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells

机译：FBXO38介导PD-1泛素化并调节T细胞的抗肿瘤免疫力

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Dysfunctional T cells in the tumour microenvironment have abnormally high expression of PD-1 and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer(1-4). The clinical success of these inhibitors highlights the need to study the mechanisms by which PD-1 is regulated. Here we report a mechanism of PD-1 degradation and the importance of this mechanism in anti-tumour immunity in preclinical models. We show that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells. FBXO38 is an E3 ligase of PD-1 that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and CD28 signalling, but led to faster tumour progression in mice owing to higher levels of PD-1 in tumour-infiltrating T cells. Anti-PD-1 therapy normalized the effect of FBXO38 deficiency on tumour growth in mice, which suggests that PD-1 is the primary target of FBXO38 in T cells. In human tumour tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescued Fbxo38 transcription and therefore downregulated PD-1 levels in PD-1(+) T cells in mice. These data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway.
机译：肿瘤微环境中功能异常的T细胞具有异常高的PD-1表达，针对PD-1或其配体的抗体抑制剂（PD-L1）已成为治疗各种类型癌症的常用药物（1-4）。这些抑制剂的临床成功凸显了研究PD-1调节机制的必要性。在这里，我们报告PD-1降解的机制，以及该机制在临床前模型中抗肿瘤免疫的重要性。我们显示表面PD-1在激活的T细胞中经历内在化，随后的泛素化和蛋白酶体降解。 FBXO38是PD-1的E3连接酶，可介导Lys48连接的多泛素化和随后的蛋白酶体降解。在T细胞中条件性敲除Fbxo38不会影响T细胞受体和CD28信号传导，但由于在肿瘤浸润性T细胞中PD-1的水平较高，导致小鼠肿瘤进展更快。抗PD-1治疗使FBXO38缺乏症对小鼠肿瘤生长的影响正常化，这表明PD-1是T细胞中FBXO38的主要靶标。在人类肿瘤组织和小鼠癌症模型中，FBXO38和Fbxo38的转录水平分别在肿瘤浸润性T细胞中下调。但是，IL-2治疗挽救了Fbxo38转录，因此下调了小鼠PD-1（+）T细胞中PD-1的水平。这些数据表明FBXO38调节PD-1的表达，并突出了另一种阻断PD-1途径的方法。

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  • 来源
    《Nature》 |2018年第7734期|130-135|共6页
  • 作者

    Meng Xiangbo; Liu Xiwei; Guo Xingdong; Jiang Shutan; Chen Tingting; Hu Zhiqiang; Liu Haifeng; Bai Yibing; Xue Manman; Hu Ronggui; Sun Shao-cong; Liu Xiaolong; Zhou Penghui; Huang Xiaowu; Wei Lai; Yang Wei; Xu Chenqi;

  • 作者单位

    Chinese Acad Sci Univ Chinese Acad Sci Shanghai Inst Biochem & Cell Biol State Key Lab Mol Biol Shanghai Sci Res Ctr CAS C Shanghai Peoples R China;

    Sun Yat Sen Univ State Key Lab Ophthalmol Guangzhou Guangdong Peoples R China;

    Fudan Univ Liver Canc Inst Zhongshan Hosp Dept Liver Surg & Transplantat Shanghai Peoples R China|Fudan Univ Key Lab Carcinogenesis & Canc Invas Minist Educ Shanghai Peoples R China;

    Chinese Acad Sci Shanghai Inst Biochem & Cell Biol CAS Ctr Excellence Mol Cell Sci State Key Lab Cell Biol Shanghai Peoples R China;

    Univ Texas MD Anderson Canc Ctr Dept Immunol Houston TX 77030 USA;

    Sun Yat Sen Univ Ctr Canc Guangzhou Guangdong Peoples R China;

    Southern Med Univ Sch Basic Med Sci Dept Pathol Guangzhou Guangdong Peoples R China|Southern Med Univ Nanfang Hosp Dept Pathol Guangzhou Guangdong Peoples R China;

    Chinese Acad Sci Univ Chinese Acad Sci Shanghai Inst Biochem & Cell Biol State Key Lab Mol Biol Shanghai Sci Res Ctr CAS C Shanghai Peoples R China|ShanghaiTech Univ Sch Life Sci & Technol Shanghai Peoples R China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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