Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Dec 20;8(1):25-37.
doi: 10.1016/j.gendis.2019.12.004. eCollection 2021 Jan.

Immune checkpoint: The novel _target for antitumor therapy

Xianghu Jiang  1 , Guohong Liu  2 , Yirong Li  1 , Yunbao Pan  1
Affiliations
Review

Immune checkpoint: The novel _target for antitumor therapy

Xianghu Jiang et al. Genes Dis. .

Abstract

Inhibitory checkpoint molecules include programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), human endogenous retrovirus-H Long terminal repeat-associating 2 (HHLA2), B7 homolog 4 protein (B7-H4), T cell membrane protein-3 (TIM-3) and Lymphocyte-activation gene 3 (LAG-3), which are up-regulated during tumorigenesis. These pathways are essential to down-regulate the immune system by blocking the activation of T cells. In recent years, immune checkpoint blockers (ICBs) against PD-1, PD-L1, CTLA-4 or TIM-3 has made remarkable progress in the clinical application, revolutionizing the treatment of malignant tumors and improving patients' overall survival. However, the efficacy of ICBs in some patients does not seem to be good enough, and more immune-related adverse events (irAEs) will inevitably occur. Therefore, biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy. There are two points in general. On the one hand, given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process, it is essential to understand their mechanisms to design the most effective individualized therapy. On the other hand, due to the lack of potent immune checkpoints, it is necessary to combine them with novel biomarkers (such as exosomes and ctDNA) and other anticancer modalities (such as chemotherapy and radiotherapy).

Keywords: Circulating tumor DNA (ctDNA); Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); Exosome; Immune checkpoint; Lymphocyte-activation gene 3 (LAG-3); Programmed cell death protein ligand 1 (PD-L1); Programmed death-1 receptor (PD-1); T cell immunoglobulin domain and mucin domain 3 (TIM-3).

PubMed Disclaimer

Figures

Fig. 1
Figure 1
T-cell activation and inactivation are multi-signal processes. The immune system needs to maintain an optimal balance between maintaining self-tolerance and clearing tumor cells. This state is regulated by a range of receptors and ligands. T cell receptor (TCR) interacts with the major histocompatibility complex (MHC) to transmit the first signal. The second antigen-independent coinhibitory signal that protects against excessive immune response includes PD-1/PD-L1(PD-L2), CTLA-4/CD80 (CD86), CD80/PD-L1, TIM-3/CEACAM (GAL-9), BTLA-4/HVEM, LAG-3/MHCll (LSECtin) and HHLA2 (TMIGD2). The second antigen-independent costimulatory signal for T lymphocyte activation includes CD40/CD40L, CD28/CD80(CD86), OX40/OX40L and CD27/CD70.
Fig. 2
Figure 2
The TCR interacts with the antigen peptide MHC complex to transmit the first signal of T cell activation. T cells activation also requires paired stimulatory molecules. The interaction of CD28 on T cells with either B7-1 (CD80) or B7-2 (CD86) on APC has been shown to transmit the second signal of T cell activation. The interaction of CD40L on T cells with CD40 on tumor cells has also been shown to transmit the second signal of T cell activation. With the continuous stimulation of tumor antigen on T cells, CTLA-4 is expressed on the surface of T cells. It competes with the CD28 receptor for binding to CD80/CD86 ligands and has a stronger affinity than CD28. CTLA-4 binding to CD80/CD86 inhibits the activation and proliferation of T cells, induces T cell apoptosis, and leads to the immune escape of cancer cells.
Fig. 3
Figure 3
The exosome is a membranous vesicle with a diameter of about 60–100 nm, which is released into the extracellular matrix by the fusion of multiple intracellular vesicles with the cell membrane. Exosomes not only transfer membrane components but also have intercellular communication. The exosome is produced by all types of cells under physiological conditions, but tumor cells are generous producers of the exosome. Exosomes can carry DNA, mRNA, lncRNAs, immune checkpoint molecules, and microRNAs. These molecules can regulate cells in a variety of ways after being transferred to _target cells.
Fig. 4
Figure 4
Anti-CTLA-4 monoclonal antibodies have a very high affinity for CTLA-4, which reduce T cell exhaustion and reinvigorate the anti-tumor response by blocking the interaction between inhibitory receptors CTLA-4 on effector T cells and its ligands B7-1 (CD80) and B7-2 (CD86) on APC. Anti-PD-1 monoclonal antibodies bind to PD-1 with high affinity, blocking its interactions with PD-L1(B7-H1) and PD-L2 (B7-DC).
Fig. 5
Figure 5
Timeline diagram of FDA-approved immune checkpoint drugs. Abbreviations: renal cell carcinoma (RCC); gastric cancer (GC); non-small Cell Lung Cancer (NSCLC); metastatic Merkel cell carcinoma (mMCC); locally advanced or metastatic (LA/M); non-squamous non-small cell lung cancer (ns-NSCLC); adenocarcinoma of the esophagogastric junction (AEG); cervical cancer (CC); primary mediastinal large B-cell lymphoma (PMBCL); urothelial carcinoma (UC); classic Hodgkin lymphoma (cHL); hepatocellular carcinoma (HCC); metastatic melanoma (mMEL); squamous cell carcinoma of the head and neck (SCCHN); wild-type (WT); unresectable or metastatic (M/UR).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lizée G., Overwijk W.W., Radvanyi L., Gao J., Sharma P., Hwu P. Harnessing the power of the immune system to _target cancer. Annu Rev Med. 2013;64:71–90. - PubMed
    1. Kean L.S., Turka L.A., Blazar B.R. Advances in _targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev. 2017;276(1):192–212. - PMC - PubMed
    1. Janakiram M., Shah U.A., Liu W., Zhao A., Schoenberg M.P., Zang X. The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev. 2017;276(1):26–39. - PMC - PubMed
    1. Ni L., Dong C. New checkpoints in cancer immunotherapy. Immunol Rev. 2017;276(1):52–65. - PubMed
    1. Andrews L.P., Marciscano A.E., Drake C.G., Vignali D.A. LAG3 (CD223) as a cancer immunotherapy _target. Immunol Rev. 2017;276(1):80–96. - PMC - PubMed
  NODES
twitter 2