CD274 molecule | Elisa - Clia - Antibody - Protein

Background

The CD274 molecule, also known as Programmed Death-Ligand 1 (PD-L1), is a critical component in the immune checkpoint pathway. Encoded by the CD274 gene located on chromosome 9p24.1, PD-L1 is primarily expressed on the surface of various cell types, including immune cells (such as T cells, B cells, dendritic cells, and macrophages) and non-immune cells (including epithelial and endothelial cells). Its expression can be upregulated in response to inflammatory signals, particularly interferon-gamma (IFN-γ). PD-L1 plays a vital role in maintaining immune homeostasis and preventing autoimmunity by regulating the activity of T cells.

PD-L1 gained significant attention in cancer immunotherapy due to its role in tumor immune evasion. Many tumors exploit the PD-1/PD-L1 pathway to suppress anti-tumor immune responses, allowing cancer cells to escape immune surveillance. Understanding the mechanisms underlying PD-L1 expression and function has led to the development of targeted therapies that block this pathway, thereby enhancing the immune system's ability to attack cancer cells.

Protein Structure

PD-L1 is a type I transmembrane protein consisting of 290 amino acids. It has an extracellular domain, a transmembrane region, and a cytoplasmic tail. The extracellular domain of PD-L1 contains immunoglobulin (Ig)-like V and C2 domains, which are essential for its interaction with the Programmed Death-1 (PD-1) receptor on T cells and other immune cells. The transmembrane region anchors PD-L1 in the cell membrane, while the cytoplasmic tail, although relatively short, is involved in intracellular signaling and regulatory functions.

The crystal structure of the PD-1/PD-L1 complex reveals that the binding of PD-L1 to PD-1 involves the IgV domain of PD-L1 and the corresponding domain of PD-1. This interaction blocks T cell receptor (TCR) signaling, leading to reduced T cell activation and proliferation. The structure of PD-L1 is crucial for its function in modulating immune responses and has been a target for designing inhibitors in cancer therapy.

Classification and Subtypes

PD-L1 is classified as part of the B7 family of immune regulatory molecules, which play roles in the modulation of immune responses through costimulatory and coinhibitory signals. Other members of this family include B7-1 (CD80), B7-2 (CD86), PD-L2 (CD273), and B7-H3 (CD276). The B7 family molecules interact with receptors on T cells to either activate or inhibit their function.

PD-L1 itself does not have subtypes, but it is closely related to PD-L2 (CD273), another ligand for PD-1. Both PD-L1 and PD-L2 bind to PD-1, but they have distinct expression patterns and regulatory mechanisms. PD-L2 is primarily expressed on dendritic cells and macrophages, whereas PD-L1 has a broader expression profile.

Function and Biological Significance

PD-L1 is a key immunoregulatory molecule that plays several crucial roles:

1. Immune Checkpoint Regulation: PD-L1 binds to the PD-1 receptor on T cells, leading to the inhibition of T cell activation and proliferation. This interaction reduces the production of cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-γ), thereby dampening immune responses.
2. Immune Homeostasis: By regulating T cell activity, PD-L1 helps maintain immune tolerance and prevent autoimmunity. It is particularly important in protecting tissues from immune-mediated damage during inflammation.
3. Tumor Immune Evasion: Many tumors upregulate PD-L1 expression to evade immune surveillance. The interaction between tumor-expressed PD-L1 and PD-1 on tumor-infiltrating lymphocytes (TILs) leads to T cell exhaustion and an impaired anti-tumor immune response. This mechanism is exploited by cancers to grow and spread unchecked by the immune system.
4. Infection and Inflammation: PD-L1 expression is induced in response to inflammatory cytokines, such as IFN-γ, during infections. This upregulation helps to control excessive immune responses and tissue damage during infection and inflammation.

Clinical Issues

The PD-1/PD-L1 pathway has become a focal point in cancer immunotherapy. Blocking this pathway with monoclonal antibodies has shown remarkable success in treating various cancers. These inhibitors, known as immune checkpoint inhibitors, include drugs such as pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq). These therapies have been approved for treating melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, and several other cancers.

However, the clinical use of PD-L1 inhibitors is not without challenges. Some issues include:

1. Immune-Related Adverse Events (irAEs): Blocking the PD-1/PD-L1 pathway can lead to overactivation of the immune system, resulting in autoimmune-like side effects. These irAEs can affect various organs, including the skin, gastrointestinal tract, liver, and endocrine glands.
2. Resistance to Therapy: Not all patients respond to PD-1/PD-L1 inhibitors, and some may develop resistance over time. Mechanisms of resistance include the upregulation of alternative immune checkpoints, loss of antigen presentation, and changes in the tumor microenvironment.
3. Biomarker Development: Identifying reliable biomarkers to predict which patients will benefit from PD-1/PD-L1 blockade is crucial. PD-L1 expression levels in tumors, the mutational burden of tumors, and the presence of tumor-infiltrating lymphocytes are some factors under investigation as potential predictive biomarkers.

Summary

CD274 (PD-L1) is a pivotal molecule in the regulation of immune responses, particularly through its interaction with the PD-1 receptor on T cells. By inhibiting T cell activity, PD-L1 plays essential roles in maintaining immune homeostasis, preventing autoimmunity, and allowing tumors to evade immune surveillance. The blockade of the PD-1/PD-L1 pathway has revolutionized cancer therapy, providing significant clinical benefits in various malignancies. However, challenges such as immune-related adverse events, resistance to therapy, and the need for reliable predictive biomarkers remain. Ongoing research aims to further elucidate the mechanisms of PD-L1 function and optimize its therapeutic targeting to enhance patient outcomes in cancer and other diseases.