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

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 mecha... Full description

Journal Title: Nature December 2018, Vol.564(7734), pp.130-135
Main Author: Meng, Xiangbo
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1476-4687 ; DOI: 10.1038/s41586-018-0756-0
Link: http://search.proquest.com/docview/2139566139/?pq-origsite=primo
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title: FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.
format: Article
creator:
  • 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
subjects:
  • Animals–Immunology
  • Female–Metabolism
  • Hek293 Cells–Immunology
  • Humans–Immunology
  • Interleukin-2–Chemistry
  • Lysine–Metabolism
  • Male–Metabolism
  • Melanoma, Experimental–Immunology
  • Mice–Immunology
  • Neoplasms–Immunology
  • Programmed Cell Death 1 Receptor–Immunology
  • Proteasome Endopeptidase Complex–Immunology
  • T-Lymphocytes–Immunology
  • Tumor Microenvironment–Immunology
  • Ubiquitination–Immunology
  • Interleukin-2
  • Pdcd1 Protein, Human
  • Pdcd1 Protein, Mouse
  • Programmed Cell Death 1 Receptor
  • Proteasome Endopeptidase Complex
ispartof: Nature, December 2018, Vol.564(7734), pp.130-135
description: 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.
language: eng
source:
identifier: E-ISSN: 1476-4687 ; DOI: 10.1038/s41586-018-0756-0
fulltext: fulltext
issn:
  • 14764687
  • 1476-4687
url: Link


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titleFBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.
creatorMeng, 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
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ispartofNature, December 2018, Vol.564(7734), pp.130-135
identifierE-ISSN: 1476-4687 ; DOI: 10.1038/s41586-018-0756-0
subjectAnimals–Immunology ; Female–Metabolism ; Hek293 Cells–Immunology ; Humans–Immunology ; Interleukin-2–Chemistry ; Lysine–Metabolism ; Male–Metabolism ; Melanoma, Experimental–Immunology ; Mice–Immunology ; Neoplasms–Immunology ; Programmed Cell Death 1 Receptor–Immunology ; Proteasome Endopeptidase Complex–Immunology ; T-Lymphocytes–Immunology ; Tumor Microenvironment–Immunology ; Ubiquitination–Immunology ; Interleukin-2 ; Pdcd1 Protein, Human ; Pdcd1 Protein, Mouse ; Programmed Cell Death 1 Receptor ; Proteasome Endopeptidase Complex
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descriptionDysfunctional 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.
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titleFBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.
authorMeng, 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
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