T cell co-stimulatory 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 demonstrated that the coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1- recruited Shp2 phosphatase, suggesting that costimulatory pathways may play unexpected roles in regulating effector T cell function and therapeutic responses to anti-PD-L1/PD-1.Abstract:
Programmed death-1 (PD-1) is a co-inhibitory 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). Here, by titrating the strength of PD-1
signaling in both biochemical reconstitution systems and in T cells, we demonstrate that the
coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1-
recruited Shp2 phosphatase. We also show that PD-1 colocalizes with the costimulatory receptor
CD28 in plasma membrane microclusters but partially segregates from the TCR. These results
reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting
that costimulatory pathways may play unexpected roles in regulating effector T cell function and
therapeutic responses to anti-PD-L1/PD-1.read more
Citations
More filters
Journal ArticleDOI
Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy.
Amrita Basu,Ganesan Ramamoorthi,Gabriella Albert,Corey Gallen,Amber Beyer,Colin Snyder,Gary K. Koski,Mary L. Disis,Brian J. Czerniecki,Kodumudi Krithika N +9 more
TL;DR: An overview of the multifaceted positive and negative effects of TH cells, with an emphasis on regulation of different TH cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy is presented.
Journal ArticleDOI
Programmed death ligand 1 signals in cancer cells
TL;DR: The recent discovery of cancer cell-intrinsic programmed death ligand 1 (PDL1) signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation as discussed by the authors .
Journal ArticleDOI
Programmed death ligand 1 signals in cancer cells
TL;DR: The recent discovery of cancer cell-intrinsic programmed death ligand 1 (PDL1) signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation as discussed by the authors .
Journal ArticleDOI
Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses
Karl L. Banta,Xiaozheng Xu,Avantika S. Chitre,Amelia Au-Yeung,Chikara Takahashi,William E. O'Gorman,Thomas D. Wu,Stephanie Mittman,Rafael Cubas,Laetitia Comps-Agrar,Amit Fulzele,Eric J. Bennett,Jane L. Grogan,Enfu Hui,Eugene Chiang,Ira Mellman +15 more
TL;DR: In this article , Chen et al. studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells and found that the effectiveness of PD-L1 or anti-TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226.
Journal ArticleDOI
A nanovaccine for antigen self-presentation and immunosuppression reversal as a personalized cancer immunotherapy strategy
Chao Liu,Xue Liu,Xinchu Xiang,Xin Pang,Siyuan Chen,Yunming Zhang,En Ren,Lili Zhang,Xuan Liu,Peng-Fei Lv,Xiaodong Wang,Wenxin Luo,Ningshao Xia,Xiaoyuan Chen,Gang Liu +14 more
TL;DR: The ASPIRE nanovaccine as discussed by the authors is derived from recombinant adenovirus-infected dendritic cells in which specific peptide-major histocompatibility complex class I (pMHC-I), anti-PD1 antibody and B7 co-stimulatory molecules are simultaneously anchored by a programmed process.
References
More filters
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.
Related Papers (5)
Engagement of CD43 Enhances Human Immunodeficiency Virus Type 1 Transcriptional Activity and Virus Production That Is Induced upon TCR/CD3 Stimulation *
Corinne Barat,Michel J. Tremblay +1 more