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

doi:10.1038/s41586-018-0756-0

	FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells
	Meng, Xiangbo 1; Liu, Xiwei 1; Guo, Xingdong 1; Jiang, Shutan 1; Chen, Tingting 2; Hu, Zhiqiang 3,4; Liu, Haifeng 5; Bai, Yibing 1; Xue, Manman 1; Hu, Ronggui 1; Sun, Shao-cong 6; Liu, Xiaolong 5; Zhou, Penghui 7; Huang, Xiaowu 3,4; Wei, Lai 2; Yang, Wei 8,9; Xu, Chenqi1,10
	2018-12-06
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
卷号	564 期号:7734 页码:130-+
发表状态	已发表
DOI	10.1038/s41586-018-0756-0
摘要	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.
收录类别	SCI ; SCIE
语种	英语
资助项目	STSMC[16JC1404800]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000452269400054
出版者	NATURE PUBLISHING GROUP
WOS关键词	INHIBITORY RECEPTOR PD-1 ; EXPRESSION ; IMMUNOTHERAPY ; IL-2 ; DYSFUNCTION ; LOCUS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/29176
专题	生命科学与技术学院_特聘教授组_许琛琦组
通讯作者	Xu, Chenqi
作者单位	1.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Mol Biol,Shanghai Sci Res Ctr,CAS C, Shanghai, Peoples R China 2.Sun Yat Sen Univ, State Key Lab Ophthalmol, Guangzhou, Guangdong, Peoples R China 3.Fudan Univ, Liver Canc Inst, Zhongshan Hosp, Dept Liver Surg & Transplantat, Shanghai, Peoples R China 4.Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Minist Educ, Shanghai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, Shanghai, Peoples R China 6.Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA 7.Sun Yat Sen Univ, Ctr Canc, Guangzhou, Guangdong, Peoples R China 8.Southern Med Univ, Sch Basic Med Sci, Dept Pathol, Guangzhou, Guangdong, Peoples R China 9.Southern Med Univ, Nanfang Hosp, Dept Pathol, Guangzhou, Guangdong, Peoples R China 10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Meng, Xiangbo,Liu, Xiwei,Guo, Xingdong,et al. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells[J]. NATURE,2018,564(7734):130-+.
APA	Meng, Xiangbo.,Liu, Xiwei.,Guo, Xingdong.,Jiang, Shutan.,Chen, Tingting.,...&Xu, Chenqi.(2018).FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.NATURE,564(7734),130-+.
MLA	Meng, Xiangbo,et al."FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells".NATURE 564.7734(2018):130-+.