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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Emerging role of PD-L1 modification in cancer immunotherapy.
TL;DR: In this paper, the PD-L1 was reported to be acetylated at Lys263 site by p300 and was deacetylated by HDAC2, which led to a reduction of the nuclear portion of the programmed cell death protein.
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Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases.
Jorge Ibañez-Vega,Constanza Vilchez,Karin Jimenez,Carlos Guevara,Paula I. Burgos,Rodrigo Naves +5 more
TL;DR: The role of the PD-1/PD-Ls pathway in neuroinflammation has been explored despite being a potential target of treatment for neurodegenerative diseases as mentioned in this paper.
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Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy
TL;DR: In this article, the molecular and functional roles of ubiquitination in key T-cell activation and checkpoint inhibitory pathways are discussed to highlight the vast possibilities that targeting ubiquitinations offers for advancing Tcell-based immunotherapies.
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RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition
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TL;DR: In this paper , the authors performed a drug repurposing library screen and discovered that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling.
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Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis.
TL;DR: In this paper, the role of ubiquitin and a fortiori, the UPS in the pathogenesis of neurodevelopmental disorders (NDD) is discussed and a possible involvement of autoinflammation in NDD pathogenesis is hypothesized.
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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