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PD-1 Receptor – Function & Immunotherapy

The PD-1 receptor is an immune checkpoint protein on T cells that regulates immune responses. Cancer cells exploit it to evade the immune system, making it a key target in modern immunotherapy.

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Things worth knowing about "PD-1 receptor"

The PD-1 receptor is an immune checkpoint protein on T cells that regulates immune responses. Cancer cells exploit it to evade the immune system, making it a key target in modern immunotherapy.

What is the PD-1 Receptor?

The PD-1 receptor (Programmed Cell Death Protein 1) is an immune checkpoint protein expressed on the surface of T cells and other immune cells. It was discovered in the early 1990s and plays a pivotal role in regulating the human immune response.

PD-1 belongs to the CD28 receptor family and is encoded by the PDCD1 gene. Its primary function is to prevent excessive immune activation, thereby maintaining a balance between effective immune defense and protection against autoimmune diseases.

Mechanism of Action

The PD-1 receptor is activated when it binds to its specific ligands – PD-L1 (Programmed Death-Ligand 1) or PD-L2 – which are expressed on various body cells and, critically, on tumor cells.

When PD-1 binds to PD-L1 or PD-L2, inhibitory signals are transmitted into the T cell, resulting in:

Reduced T cell activity and proliferation
Decreased cytokine production (signaling molecules of the immune system)
Increased T cell exhaustion in chronic disease states
Promotion of immune tolerance toward the body's own tissues

Under normal circumstances, this mechanism is essential for preventing autoimmune reactions. In cancer, however, tumor cells exploit this pathway to evade detection and destruction by the immune system.

Significance in Oncology

Many cancer cells overexpress the ligand PD-L1, enabling them to suppress T cell activity and escape immune surveillance. This mechanism of immune evasion has been documented across numerous tumor types, including:

Non-small cell lung cancer (NSCLC)
Malignant melanoma (skin cancer)
Renal cell carcinoma
Bladder cancer (urothelial carcinoma)
Hodgkin lymphoma
Head and neck squamous cell carcinoma

The discovery of this mechanism laid the foundation for the development of a new class of cancer drugs known as checkpoint inhibitors.

PD-1 Inhibitors as Immunotherapy

Based on the PD-1 receptor, monoclonal antibodies have been developed that block the receptor or its ligands, thereby restoring the immune response against tumor cells. These agents are known as PD-1 inhibitors or anti-PD-1 antibodies.

Approved PD-1 Inhibitors (Examples)

Pembrolizumab (Keytruda®): directly blocks PD-1
Nivolumab (Opdivo®): directly blocks PD-1
Atezolizumab (Tecentriq®): blocks PD-L1
Durvalumab (Imfinzi®): blocks PD-L1

These agents have revolutionized the treatment of various cancers and, in some cases, have led to durable remissions even in advanced disease stages.

Role in Autoimmune Diseases and Infectious Diseases

Beyond oncology, the PD-1 receptor is also significant in other medical contexts:

Autoimmune diseases: Deficient PD-1 signaling can increase susceptibility to autoimmune conditions such as systemic lupus erythematosus or rheumatoid arthritis.
Chronic infections: In diseases such as HIV or chronic hepatitis B, elevated PD-1 expression on exhausted T cells impairs immune control of the infection.
Transplant medicine: The PD-1 axis plays a role in promoting tolerance toward transplanted organs.

Side Effects of PD-1 Blockade

Because PD-1 inhibitors broadly activate the immune system, they can also attack healthy tissues. Typical immune-mediated adverse effects include:

Skin rash and itching (dermatitis)
Lung inflammation (pneumonitis)
Liver inflammation (hepatitis)
Thyroid dysfunction (hypothyroidism or hyperthyroidism)
Intestinal inflammation (colitis)
Rarely: inflammation of the heart (myocarditis) or nervous system

These side effects require close medical monitoring and are treated with corticosteroids when necessary.

Diagnostic Relevance: PD-L1 Testing

Before initiating checkpoint inhibitor therapy, the PD-L1 expression in tumor tissue is assessed by immunohistochemistry (IHC) in many cancer types. A high PD-L1 score may indicate a better response to therapy, although it is not the sole predictive biomarker.

References

Ishida Y. et al. - Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO Journal, 11(11):3887-3895, 1992.
Topalian SL, Drake CG, Pardoll DM. - Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 27(4):450-461, 2015. PubMed PMID: 25858804.
World Health Organization (WHO) - Cancer Overview and Immunotherapy. Available at: https://www.who.int/news-room/fact-sheets/detail/cancer

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