Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targetin...

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Published inJournal of experimental & clinical cancer research Vol. 40; no. 1; pp. 1 - 22
Main Authors Zhang, Hao, Dai, Ziyu, Wu, Wantao, Wang, Zeyu, Zhang, Nan, Zhang, Liyang, Zeng, Wen-Jing, Liu, Zhixiong, Cheng, Quan
Format Journal Article
LanguageEnglish
Published London BioMed Central Ltd 04.06.2021
BioMed Central
BMC
Subjects
Antigens
Apoptosis
B cells
Biomarkers
Breast cancer
Cancer
Cancer immunotherapy
Cancer therapies
Care and treatment
CTLA-4
DNA methylation
Drug intervention
Epigenetics
Genes
Immunoglobulins
Immunotherapy
Ipilimumab
Kinases
Liver cancer
Localization
Lung cancer
Lymphocytes
Lymphoma
Melanoma
PD-L1
Proteins
Regulatory mechanism
Review
RNA
T cells
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Summary:The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.
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ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-021-01987-7