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
Citations
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Journal ArticleDOI
Immune checkpoint signaling and cancer immunotherapy.
Xing He,Chenqi Xu,Chenqi Xu +2 more
TL;DR: Regulation of immune checkpoint signaling at multiple levels is discussed to provide an overview of the current understanding of checkpoint biology and includes the regulation of surface expression levels for known immune checkpoint proteins via surface delivery, internalization, recycling, and degradation.
Journal ArticleDOI
The role of ubiquitination in tumorigenesis and targeted drug discovery
TL;DR: The latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance are summarized and potential therapeutic targets for cancer are reviewed.
Journal ArticleDOI
Revisiting the PD-1 pathway
TL;DR: This review provides an overview of recent advances in understanding the interactions and signaling of PD-1 and its ligands and discusses the implications of these new discoveries and the gaps that remain to be filled.
Journal ArticleDOI
TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma.
Xiaochen Wang,Qifeng He,Qifeng He,Haiyuan Shen,Anliang Xia,Anliang Xia,Wenfang Tian,Weiwei Yu,Beicheng Sun,Beicheng Sun +9 more
TL;DR: Downregulating TOX expression improves the antitumor function of CD8+ T cells, which shows synergetic role with anti-PD1 therapy, highlighting a promising strategy for enhancement of cancer immunotherapy.
Book ChapterDOI
Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond.
Luoyan Ai,Antao Xu,Jie Xu +2 more
TL;DR: Clinically, antibodies targeting PD-1/PD-L1 reinvigorate the "exhausted" T cells in TME and show remarkable objective response and durable remission with acceptable toxicity profile in large numbers of tumors such as melanoma, lymphoma, and mismatch-repair deficient tumors.
References
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Journal ArticleDOI
Defining CD8 + T cells that provide the proliferative burst after PD-1 therapy
Se Jin Im,Masao Hashimoto,Michael Y. Gerner,Michael Y. Gerner,Junghwa Lee,Haydn T. Kissick,Matheus Carvalho Bürger,Qiang Shan,J. Scott Hale,Judong Lee,Tahseen H. Nasti,Arlene H. Sharpe,Arlene H. Sharpe,Gordon J. Freeman,Ronald N. Germain,Helder I. Nakaya,Hai-Hui Xue,Rafi Ahmed +17 more
TL;DR: A population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus is identified and its findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD- 1-directed immunotherapy in chronic infections and cancer.
Journal ArticleDOI
IL-2: The First Effective Immunotherapy for Human Cancer
TL;DR: The genetic modification of T cells with genes encoding αβ TCRs or chimeric Ag receptors and the administration of these cells after expansion in IL-2 have extended effective cell transfer therapy to other cancer types.
Journal ArticleDOI
Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade
Spencer C. Wei,Jacob H. Levine,Alexandria P. Cogdill,Yang Zhao,Nana Ama A.S. Anang,Miles C. Andrews,Padmanee Sharma,Jing Wang,Jennifer A. Wargo,Dana Pe'er,James P. Allison +10 more
TL;DR: These findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms, and that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations.
Journal ArticleDOI
Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection.
Michael A. Paley,Daniela C. Kroy,Pamela M. Odorizzi,Jonathan B. Johnnidis,Douglas V. Dolfi,Burton E. Barnett,Elizabeth K. Bikoff,Elizabeth J. Robertson,Georg M. Lauer,Steven L. Reiner,E. John Wherry +10 more
TL;DR: It is demonstrated that the T-box transcription factors T-bet and Eomesodermin differentially regulate two phenotypically and functionally distinct subsets of antiviral CD8+ T cells in mice, which may be important for antiviral immunity during chronic viral infections in humans.
Journal ArticleDOI
T Cell Dysfunction in Cancer.
TL;DR: The current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how the emerging understanding may be utilized to develop personalized strategies to restore antitumor immunity are discussed.
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