T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.
Enfu Hui,Jeanne Cheung,Jing Zhu,Xiaolei Su,Marcus J. Taylor,Heidi J.A. Wallweber,Dibyendu Kumar Sasmal,Jun Huang,Jeong M. Kim,Ira Mellman,Ronald D. Vale +10 more
TLDR
It is shown that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.Abstract:
Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.read more
Citations
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Journal ArticleDOI
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
TL;DR: The current state of understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, is reviewed, and conceptual gaps in knowledge are highlighted.
Journal ArticleDOI
A guide to cancer immunotherapy: from T cell basic science to clinical practice.
TL;DR: This guide to cancer immunotherapy provides a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation.
Journal ArticleDOI
Approaches to treat immune hot, altered and cold tumours with combination immunotherapies
Jérôme Galon,Daniela Bruni +1 more
TL;DR: A panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours is provided and the impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
Journal ArticleDOI
Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response
Chen Gang,Alexander C. Huang,Wei Zhang,Wei Zhang,Gao Zhang,Wu Min,Wei Xu,Zi-Li Yu,Jiegang Yang,Jiegang Yang,Beike Wang,Beike Wang,Honghong Sun,Hou-Fu Xia,Qiwen Man,Wenqun Zhong,Wenqun Zhong,Leonardo F. Antelo,Bin Wu,Xuepeng Xiong,Xiaoming Liu,Lei Guan,Lei Guan,Ting Li,Ting Li,Shujing Liu,Ruifeng Yang,Youtao Lu,Liyun Dong,Suzanne McGettigan,Rajasekharan Somasundaram,Ravi Radhakrishnan,Gordon B. Mills,Yiling Lu,Junhyong Kim,Youhai H. Chen,Haidong Dong,Yi-Fang Zhao,Giorgos C. Karakousis,Tara C. Mitchell,Lynn M. Schuchter,Meenhard Herlyn,E. John Wherry,Xiaowei Xu,Wei Guo +44 more
TL;DR: It is reported that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface, suggesting a mechanism by which tumours could evade the immunesystem, and the potential application ofExosomal PD- L1 to monitor patient responses to checkpoint therapies.
Journal ArticleDOI
Regulation and Function of the PD-L1 Checkpoint
TL;DR: The roles of the PD-1-PD-L1 axis in cancer is reviewed, focusing on recent findings on the mechanisms that regulate PD-L 1 expression at the transcriptional, posttranscriptional, and protein level, to inform the design of more precise and effective cancer immune checkpoint therapies.
References
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Journal ArticleDOI
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Journal ArticleDOI
The blockade of immune checkpoints in cancer immunotherapy
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Journal ArticleDOI
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
Gordon J. Freeman,Andrew J. Long,Yoshiko Iwai,Karen Bourque,Tatyana Chernova,Hiroyuki Nishimura,Lori Fitz,Nelly Malenkovich,Taku Okazaki,Michael C. Byrne,Heidi F. Horton,Lynette A. Fouser,Laura L. Carter,Vincent Ling,Michael R Bowman,Beatriz M. Carreno,Mary Collins,Clive Wood,Tasuku Honjo +18 more
TL;DR: It is reported here that the ligand of PD-1 (PD-L1), an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells, is a member of the B7 gene family.
Journal ArticleDOI
PD-1 and its ligands in tolerance and immunity
TL;DR: Current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential are discussed and an inhibitory bidirectional interaction between PD-L1 and B7-1 is discovered, revealing new ways the B7:CD28 family regulates T cell activation and tolerance.
Journal ArticleDOI
Oncology Meets Immunology: The Cancer-Immunity Cycle
TL;DR: Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer and may be more effective in combination with agents that target other steps of the cycle.
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