TY - JOUR
T1 - Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint
AU - Tang, Ting Ting
AU - Cheng, Xiang
AU - Truong, Billy
AU - Sun, Li Zhe
AU - Yang, Xiao Feng
AU - Wang, Hong
N1 - Publisher Copyright:
© 2020
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - CD40/CD40L
KW - effector function
KW - immune checkpoint
KW - molecular basis
KW - therapeutic implications
UR - http://www.scopus.com/inward/record.url?scp=85094856222&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2020.107709
DO - 10.1016/j.pharmthera.2020.107709
M3 - Review article
C2 - 33091428
AN - SCOPUS:85094856222
SN - 0163-7258
VL - 219
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
M1 - 107709
ER -