FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. (6th December 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Nature. Volume 564:Number 7734(2018)
• Page Start: 130
• Page End: 135
• Publication Date: 2018-12-06
• Subjects: Science -- Periodicals; 505
• DOI: 10.1038/s41586-018-0756-0
• Languages: English
• ISSNs: 0028-0836

Abstract

Abstract 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 cancer1–4 . 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 ofFbxo38 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 ofFBXO38 andFbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescuedFbxo38 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. PD-1 undergoes internalization, FBXO38-mediated ubiquitination and proteasome degradation in activated T cells, and inhibition of this pathway dampens anti-tumour immunity of T cells.