Your browser doesn't support javascript.
loading
Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint.
Tang, TingTing; Cheng, Xiang; Truong, Billy; Sun, LiZhe; Yang, XiaoFeng; Wang, Hong.
Afiliação
  • Tang T; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
  • Cheng X; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Truong B; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
  • Sun L; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Cardiovascular Medicine, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
  • Yang X; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
  • Wang H; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. Electronic address: hong.wang@temple.edu.
Pharmacol Ther ; 219: 107709, 2021 03.
Article em En | MEDLINE | ID: mdl-33091428
The CD40 receptor and its ligand CD40L is one of the most critical molecular pairs of the stimulatory immune checkpoints. Both CD40 and CD40L have a membrane form and a soluble form generated by proteolytic cleavage or alternative splicing. CD40 and CD40L are widely expressed in various types of cells, among which B cells and myeloid cells constitutively express high levels of CD40, and T cells and platelets express high levels of CD40L upon activation. CD40L self-assembles into functional trimers which induce CD40 trimerization and downstream signaling. The canonical CD40/CD40L signaling is mediated by recruitment of TRAFs and NF-κB activation, which is supplemented by signal pathways such as PI3K/AKT, MAPKs and JAK3/STATs. CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells via two-way signaling. CD40/CD40L interaction also participates in regulating thrombosis, tissue inflammation, hematopoiesis and tumor cell fate. Because of its essential role in immune activation, CD40/CD40L interaction has been regarded as an attractive immunotherapy target. In recent years, significant advance has been made in CD40/CD40L-targeted therapy. Various types of agents, including agonistic/antagonistic monoclonal antibodies, cellular vaccines, adenoviral vectors and protein antagonist, have been developed and evaluated in early-stage clinical trials for treating malignancies, autoimmune diseases and allograft rejection. In general, these agents have demonstrated favorable safety and some of them show promising clinical efficacy. The mechanisms of benefits include immune cell activation and tumor cell lysis/apoptosis in malignancies, or immune cell inactivation in autoimmune diseases and allograft rejection. This review provides a comprehensive overview of the structure, processing, cellular expression pattern, signaling and effector function of CD40/CD40L checkpoint molecules. In addition, we summarize the progress, targeted diseases and outcomes of current ongoing and completed clinical trials of CD40/CD40L-targeted therapy.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Autoimunes / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Autoimunes / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article