CD274

Official Full Name

CD274 molecule

Organism

Homo sapiens

GeneID

29126

Background

This gene encodes an immune inhibitory receptor ligand that is expressed by hematopoietic and non-hematopoietic cells, such as T cells and B cells and various types of tumor cells. The encoded protein is a type I transmembrane protein that has immunoglobulin V-like and C-like domains. Interaction of this ligand with its receptor inhibits T-cell activation and cytokine production. During infection or inflammation of normal tissue, this interaction is important for preventing autoimmunity by maintaining homeostasis of the immune response. In tumor microenvironments, this interaction provides an immune escape for tumor cells through cytotoxic T-cell inactivation. Expression of this gene in tumor cells is considered to be prognostic in many types of human malignancies, including colon cancer and renal cell carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

Synonyms

B7-H; B7H1; PDL1; PD-L1; hPD-L1; PDCD1L1; PDCD1LG1;

Bio Chemical Class

mRNA target

Protein Sequence

MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET

Open

Disease

Hepatitis virus infection

Approved Drug

6 +

Clinical Trial Drug

37 +

Discontinued Drug

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Detailed Information

The CD274 gene is located on chromosome 9p24.1 and was first discovered by Chinese scientist Professor Chen Lieping in 1999. This gene codes for a 290 amino acid protein with a significant structure including one IgV-like domain and one IgC-like domain. PD-L1, a member of the B7 family, is structurally like other proteins that control immune responses but serves as a negative regulator of immune activation alone.

Structurally, PD-L1 is a type I transmembrane protein—that is, one that can send signals into the cell via spanning the cellular membrane Mostly expressed on activated T-cells, B-cells, and macrophages, binding to PD-1 causes a cascade of inhibitory signals to reduce immune activity. This suppression lowers the risk of immune cells attacking the body's own tissues, therefore preserving peripheral tolerance and preventing autoimmunity.

Mechanism of PD-L1/PD-1 Interaction

Maintaining immunological equilibrium depends on the PD-L1/PD-1 interaction, however when taken over by tumors it becomes a double-edged blade. On the surface of effector T-cells, which target either malignant or infected cells—PD-L1 hooks themselves to PD-1. Tyrosine residues in the immunoreceptor tyrosine-based switch motif (ITSM) in PD-1's cytoplasmic domain phosphorylated upon PD-L1's interaction to PD-1. This phosphorylation process attracts the phosphatase SHP-2, which dephosphorylates important proteins engaged in the T-cell activation pathway, hence producing T-cell inhibition.

Within the framework of cancer, this inhibition helps tumors to avoid the immune response as T-cells meant to target and destroy tumor cells become inactive. By upregulating PD-L1 expression, tumor cells often use this pathway to improve their capacity to quell T-cell responses. Many different forms of tumors, including melanoma, gastric cancer, ovarian cancer, renal cell carcinoma, and NSCLC, have shown this overexpression.

Figure 1 describes the mechanism by which blocking the PD-1/PD-L1/PD-L2 pathway using monoclonal antibodies can enhance the immune system ability to fight cancer. Figure 1. Human cancer immunotherapy with anti-PD-1 and anti-PD-L1/L2 antibodies. (Ohaegbulam KC, et al., 2015)

Clinical Implications

In many malignancies, the expression of PD-L1 on tumor cells has evolved into a crucial indicator of prognosis and therapeutic choice. For instance, poor prognosis in melanoma and NSCLC as well as various other cancers has been linked to high degrees of PD-L1 expression. Studies have shown that PD-L1 expression predicts patient outcomes and links with tumor aggressiveness.

Early-stage tumors often display high levels of PD-L1 expression on tumor cells, according to a study included melanoma patients. This implies that PD-L1 is component of an adaptive strategy tumors adopt to escape the immune system. Studies by Taube et al. and Massi et al., for example, showed that PD-L1-positive melanoma cells are more invasive and multiply more quickly than PD-L1-negative cells, therefore confirming the significance of PD-L1 as a major actor in tumor development.

In NSCLC, PD-L1 expression has been linked to more advanced disease stages and worse patient outcomes. Patients with PD-L1-positive tumors often had worse overall survival rates when compared to those with PD-L1-negative tumors, Zhang et al. noted. PD-L1 immunohistochemistry is becoming increasingly used as a predictive technique as it gives oncologists important information to direct therapy choices.

Immunotherapy and PD-L1 Targeted Treatments

Cancer immunotherapy has advanced remarkably since the PD-L1/PD-1 pathway was identified as a mechanism of tumour immune evasion. Blocking this pathway has showed promise for treating a range of malignancies, including those with high levels of PD-L1 expression, using checkpoint inhibitors as pembrolizumab and nivolumab.

Anti-PD-1/PD-L1 treatments have greatly improved general survival rates and progression-free survival in melanoma. Clinical studies where anti-PD-L1 antibodies were used to treat metastatic melanoma suggest that patients with high PD-L1 expression react more favourably to these therapies. Further underlining the therapeutic worth of targeting this pathway, a 2015 research by Freeman-Keller found that high PD-L1 expression was an independent risk factor for reduced overall survival in patients with melanoma.

Clinical studies conducted in NSCLC have revealed individuals treated with pembrolizumab enjoy longer progression-free survival (PFS) and overall survival than those treated with conventional treatment. With better objective response rates (ORR) and less adverse effects, a seminal research by Reck found that pembrolizumab was much more successful than platinum-based chemotherapy in patients with PD-L1-positive tumors. Other trials, like those by Garon, which revealed an ORR of 19.4% and a median PFS of 6.3 months in patients treated with pembrolizumab, have validated these results.

References:

MCLAUGHLIN J, HAN G, SCHALPER K A, et al. Quantitative assessment of the heterogeneity of PD- L1 expression in non-small cell lung cancer. JAMA Oncol, 2016, 2(1):46-54.
Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive nonsmall-cell lung cancer. N Engl J Med, 2016, 375: 1823-1833.
Zhang MH, Dong YD, Liu HT, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1, 901 patients. Sci Rep, 2016 6: 37933.
Ohaegbulam KC, Assal A, Lazar-Molnar E, et al. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24-33.

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