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

Nature. 2018 Dec;564(7734):130-135. doi: 10.1038/s41586-018-0756-0.

Xiangbo Meng ¹, Xiwei Liu ¹, Xingdong Guo ¹, Shutan Jiang ¹, Tingting Chen ², Zhiqiang Hu ³ ⁴, Haifeng Liu ⁵, Yibing Bai ¹, Manman Xue ¹, Ronggui Hu ¹, Shao-Cong Sun ⁶, Xiaolong Liu ⁵, Penghui Zhou ⁷, Xiaowu Huang ³ ⁴, Lai Wei ², Wei Yang ⁸ ⁹, Chenqi Xu ¹⁰ ¹¹

Affiliations

1 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.
2 State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.
3 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
4 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China.
5 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
6 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7 Sun Yat-sen University Cancer Center, Guangzhou, China.
8 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
9 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
10 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. cqxu@sibcb.ac.cn.
11 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. cqxu@sibcb.ac.cn.

PMID: 30487606 DOI: 10.1038/s41586-018-0756-0

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 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.

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