Journal ArticleDOI
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,Bai Yibing,Manman Xue,Ronggui Hu,Shao Cong Sun,Xiaolong Liu,Penghui Zhou,Xiaowu Huang,Lai Wei,Wei Yang,Chenqi Xu,Chenqi Xu +17 more
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TLDR
It is shown that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells, and inhibition of this pathway dampens anti-tumour immunity of T cells.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.read more
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Journal ArticleDOI
Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave
TL;DR: In this article, the role of posttranslational modifications (PTMs) in PD-L1 expression, trafficking, and antitumor immune response is discussed. And the implication of PTMs in anti-PD-1/PD-L 1 therapies are discussed.
Journal ArticleDOI
Inborn Errors of Immunity and Their Phenocopies: CTLA4 and PD-1
Yu-Fei Hao,Matthew C. Cook +1 more
TL;DR: This work considers IEIs arising from rare genetic variants in CTLA4 and PDCD1 and compares clinical and laboratory manifestations arising as drug-induced phenocopies in cancer patients treated with immune checkpoint inhibitors (ICI) and identifies outstanding questions regarding mechanism of disease.
Journal ArticleDOI
Strategies for developing PD-1 inhibitors and future directions.
TL;DR: A review of PD-1/PD-L1 inhibitors can be found in this article , where the authors discuss the crystal structure of PD1 and L1/L1, and physiological and pathological roles played by PD1.
Book ChapterDOI
Regulation of Cancer Immune Checkpoint: Mono- and Poly-Ubiquitination: Tags for Fate
TL;DR: Ubiquitination, as one of the most important posttranslational modification of proteins, also modulates the expression, intracellular trafficking, subcellular and membranous location of immune checkpoints, regulating the immune surveillance of T cells to tumors.
Journal ArticleDOI
FBXO38 Drives PD-1 to Destruction.
Taryn M. Serman,Michaela U. Gack +1 more
TL;DR: The E3 ubiquitin ligase FBXO38 is identified as a crucial regulator of PD-1 protein turnover in T cells, providing a novel mechanism for potential use in cancer immunotherapy.
References
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Journal ArticleDOI
Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion
Haidong Dong,Scott E. Strome,Diva R. Salomao,Hideto Tamura,Fumiya Hirano,Dallas B. Flies,Patrick C. Roche,Jun Lu,Gefeng Zhu,Koji Tamada,Vanda A. Lennon,Esteban Celis,Lieping Chen +12 more
TL;DR: It is reported here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1 and the findings have implications for the design of T cell–based cancer immunotherapy.
Journal ArticleDOI
The future of immune checkpoint therapy
Padmanee Sharma,James P. Allison +1 more
TL;DR: The way forward for this class of novel agents lies in the ability to understand human immune responses in the tumor microenvironment, which will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
Journal ArticleDOI
The Ubiquitin Code
David Komander,Michael Rape +1 more
TL;DR: The structure, assembly, and function of the posttranslational modification with ubiquitin, a process referred to as ubiquitylation, controls almost every process in cells.
Journal ArticleDOI
Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade
TL;DR: The results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 andPD-L may provide a promising strategy for specific tumor immunotherapy.
Journal ArticleDOI
Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.
TL;DR: The results suggest that activation of the PD‐1 gene may be involved in the classical type of programmed cell death.
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