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

Xiangbo Meng, Xiwei Liu, Xingdong Guo, Shutan Jiang, Tingting Chen, Zhiqiang Hu, Haifeng Liu, Yibing Bai, Manman Xue, Ronggui Hu, Shao-cong Sun, Xiaolong Liu, Penghui Zhou, Xiaowu Huang, Lai Wei, Wei Yang and Chenqi Xu ()
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Xiangbo Meng: University of Chinese Academy of Sciences
Xiwei Liu: University of Chinese Academy of Sciences
Xingdong Guo: University of Chinese Academy of Sciences
Shutan Jiang: University of Chinese Academy of Sciences
Tingting Chen: Sun Yat-sen University
Zhiqiang Hu: Fudan University
Haifeng Liu: Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
Yibing Bai: University of Chinese Academy of Sciences
Manman Xue: University of Chinese Academy of Sciences
Ronggui Hu: University of Chinese Academy of Sciences
Shao-cong Sun: The University of Texas MD Anderson Cancer Center
Xiaolong Liu: Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
Penghui Zhou: Sun Yat-sen University Cancer Center
Xiaowu Huang: Fudan University
Lai Wei: Sun Yat-sen University
Wei Yang: Southern Medical University
Chenqi Xu: University of Chinese Academy of Sciences

Nature, 2018, vol. 564, issue 7734, 130-135

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 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.

Keywords: HEK293FT Cells; Negative Selection Magnetic Bead; Fbxo7 Expression; FBXO7 Gene; Jurkat Cells (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0756-0

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