1. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.
- Author
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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, and Xu, Chenqi
- 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 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. 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. [ABSTRACT FROM AUTHOR]- Published
- 2018
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