State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.
Nature. 2018 Dec;564(7734):130-135. doi: 10.1038/s41586-018-0756-0. Epub 2018 Nov 28.
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. 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.
肿瘤微环境中的功能失调 T 细胞异常高表达 PD-1，针对 PD-1 或其配体（PD-L1）的抗体抑制剂已成为治疗各种类型癌症的常用药物。这些抑制剂的临床成功突出表明需要研究 PD-1 调控的机制。在这里，我们报告了 PD-1 降解的一种机制，以及该机制在临床前模型中抗肿瘤免疫中的重要性。我们表明，激活的 T 细胞中表面 PD-1 会发生内化，随后发生泛素化和蛋白酶体降解。FBXO38 是 PD-1 的 E3 连接酶，介导 Lys48 连接的多泛素化和随后的蛋白酶体降解。T 细胞中 Fbxo38 的条件敲除不影响 T 细胞受体和 CD28 信号，但由于肿瘤浸润性 T 细胞中 PD-1 水平较高，导致小鼠肿瘤进展更快。抗 PD-1 治疗使 FBXO38 缺乏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，肿瘤浸润性 T 细胞中 FBXO38 和 Fbxo38 的转录水平分别下调。然而，IL-2 治疗挽救了 Fbxo38 的转录，从而降低了小鼠 PD-1 T 细胞中的 PD-1 水平。这些数据表明 FBXO38 调节 PD-1 的表达，并强调了阻断 PD-1 途径的另一种方法。
