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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
FBXL6 is dysregulated in keloids and promotes keloid fibroblast growth by inducing c‐Myc expression
TL;DR: F-box and leucine-rich repeat protein 6 (FBXL6) could promote the growth of keloid fibroblasts by inducing c-MYC expression, which could be targeted in keloids treatment.
Journal ArticleDOI
High Mobility Group Protein B1 Decreases Surface Localization of PD-1 to Augment T-cell Activation
TL;DR: In this paper , the authors found that highmobility group protein B1 (HMGB1) release induced by chemotherapy in patients with non-small cell lung cancer was negatively correlated with PD-1 expression on CD8+ T cells.
Journal ArticleDOI
miR-4759 suppresses breast cancer through immune checkpoint blockade
Paolo Landi,Clara Teixeira +1 more
TL;DR: In this article , a novel microRNA miR-4759 targeting the PD-L1 gene through two binding motifs in the 3' untranslated region (3'-UTR).
Journal ArticleDOI
Expression of periodontitis susceptibility genes in human gingiva using single-cell RNA sequencing.
TL;DR: These findings seem to suggest that innate cell dysfunction is linked to disease susceptibility, as diverse populations contributing to disease pathogenesis, with macrophages expressing a higher number of the analysed disease-associated genes.
Journal ArticleDOI
BRCA1 deficiency in mature CD8+ T lymphocytes impairs antitumor immunity
Bogang Wu,Leilei Qi,Huai-Chin Chiang,Haihui Pan,Xiaowen Zhang,Alexandra Greenbaum,Elizabeth Stark,Li Ju Wang,Ying Chen,Bassem R. Haddad,Dionyssia Clagett,Claudine Isaacs,Richard M. Elledge,Anelia Horvath,Yanfen Hu,Rong Li +15 more
TL;DR: In this paper , the authors reported that mouse Brca1 knockout in mature T lymphocytes compromises host antitumor immune response to transplanted syngeneic mouse mammary tumors and suggested that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.
References
More filters
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.
Related Papers (5)
Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity
Chia Wei Li,Seung Oe Lim,Weiya Xia,Heng Huan Lee,Li Chuan Chan,Li Chuan Chan,Chu Wei Kuo,Kay-Hooi Khoo,Shih Shin Chang,Jong Ho Cha,Taewan Kim,Jennifer L. Hsu,Jennifer L. Hsu,Jennifer L. Hsu,Yun Wu,Jung Mao Hsu,Hirohito Yamaguchi,Qingqing Ding,Yan Wang,Jun Yao,Cheng Chung Lee,Hsing Ju Wu,Aysegul A. Sahin,James P. Allison,Dihua Yu,Gabriel N. Hortobagyi,Mien Chie Hung +26 more
CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity
Marian L. Burr,Marian L. Burr,Marian L. Burr,Christina E. Sparbier,Yih-Chih Chan,James C Williamson,Katherine Woods,Paul A. Beavis,Paul A. Beavis,Enid Y.N. Lam,Enid Y.N. Lam,Melissa A. Henderson,Melissa A. Henderson,Charles C. Bell,Charles C. Bell,Sabine Stolzenburg,Omer Gilan,Omer Gilan,Stuart Bloor,Tahereh Noori,David W. Morgens,Michael C. Bassik,Paul J Neeson,Paul J Neeson,Andreas Behren,Phillip K. Darcy,Phillip K. Darcy,Sarah-Jane Dawson,Sarah-Jane Dawson,Ilia Voskoboinik,Ilia Voskoboinik,Joseph A. Trapani,Joseph A. Trapani,Jonathan Cebon,Paul J. Lehner,Mark A. Dawson +35 more