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PD-1 Axis: Immune Checkpoint & Cancer Therapy

The PD-1 axis is an immune checkpoint pathway that regulates T-cell activity. Cancer cells exploit this mechanism to evade immune system detection and destruction.

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Things worth knowing about "PD-1 Axis"

The PD-1 axis is an immune checkpoint pathway that regulates T-cell activity. Cancer cells exploit this mechanism to evade immune system detection and destruction.

What Is the PD-1 Axis?

The PD-1 axis is a key signaling pathway of the immune system that controls the activity of T cells -- the immune system's primary attack cells. The term refers to the interaction between the receptor PD-1 (Programmed Cell Death Protein 1) and its binding partners, the ligands PD-L1 and PD-L2. Together, these molecules form the PD-1 axis.

Under normal physiological conditions, the PD-1 axis acts as a critical brake on the immune system. It prevents excessive immune responses and protects healthy tissue from being attacked by the body's own immune cells. However, in many cancers, tumor cells hijack this mechanism to escape immune surveillance and destruction -- a phenomenon known as immune evasion.

Biological Foundations

The PD-1 Receptor

PD-1 is a protein expressed on the surface of activated T cells. It functions as an immune checkpoint -- a regulatory switch that limits the strength and duration of an immune response. When PD-1 binds to its ligand, the T cell is inhibited and its activity is reduced.

The Ligands PD-L1 and PD-L2

PD-L1 (also known as CD274 or B7-H1) and PD-L2 (also known as CD273 or B7-DC) are the natural binding partners of PD-1. PD-L1 is expressed on a wide variety of body cells and immune cells and plays the most significant clinical role. PD-L2 expression is more restricted, primarily found on certain immune cells.

Function in a Healthy Organism

In healthy individuals, the PD-1 axis helps prevent autoimmune diseases. It ensures that T cells are properly deactivated after resolving an infection, preventing them from attacking healthy tissue. This self-tolerance mechanism is essential for maintaining immune balance.

Role in Cancer

Many tumor cells develop the ability to overexpress PD-L1 on their surface. This sends a false inhibitory signal to approaching T cells: the T cells bind PD-L1 on tumor cells via their PD-1 receptor, become suppressed, and can no longer effectively destroy the tumor. This process is referred to as immune escape.

Cancer types where PD-L1 overexpression is frequently observed include:

Non-small cell lung cancer (NSCLC)
Malignant melanoma (skin cancer)
Renal cell carcinoma
Bladder cancer (urothelial carcinoma)
Classical Hodgkin lymphoma
Triple-negative breast cancer

Therapeutic Relevance: Checkpoint Inhibitors

The discovery of the PD-1 axis has transformed cancer therapy. Immune checkpoint inhibitors are antibodies that specifically block either the PD-1 receptor or the PD-L1 ligand, thereby lifting the inhibition of T cells and allowing the immune system to attack tumor cells once again.

PD-1 Inhibitors

Antibodies that bind to PD-1 and block its interaction with PD-L1 and PD-L2. Examples of approved agents include:

Pembrolizumab (Keytruda®)
Nivolumab (Opdivo®)
Cemiplimab (Libtayo®)

PD-L1 Inhibitors

Antibodies that bind to PD-L1 and block its interaction with PD-1. Examples include:

Atezolizumab (Tecentriq®)
Durvalumab (Imfinzi®)
Avelumab (Bavencio®)

Diagnostic Relevance: PD-L1 Testing

Before initiating checkpoint inhibitor therapy, many treatment protocols require assessment of the PD-L1 expression status of the tumor. This is determined by immunohistochemical staining of tumor tissue. The proportion of PD-L1-positive tumor cells is reported as the Tumor Proportion Score (TPS) or Combined Positive Score (CPS). A high PD-L1 expression level is associated with better response to immunotherapy in certain cancer types.

Side Effects and Risks of Checkpoint Inhibitor Therapy

Because checkpoint inhibitors release the natural brakes of the immune system, they can trigger immune-related adverse events (irAEs) that may affect various organs:

Skin (rash, itching)
Gastrointestinal tract (colitis, diarrhea)
Liver (immune-mediated hepatitis)
Lungs (pneumonitis)
Endocrine glands (thyroiditis, hypophysitis)

These side effects can range from mild to life-threatening and require close medical monitoring, as well as treatment with corticosteroids in more severe cases.

Research and Future Directions

The PD-1 axis remains one of the most actively researched areas in oncology and immunology. Current studies are investigating combination therapies (e.g., PD-1 inhibitors combined with CTLA-4 blockade or chemotherapy), novel biomarkers to predict treatment response, and the role of the PD-1 axis in chronic infectious diseases such as HIV and hepatitis.

References

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350-1355. doi:10.1126/science.aar4060
Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nature Reviews Cancer. 2016;16(5):275-287.
National Cancer Institute (NCI). Immune Checkpoint Inhibitors. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors (accessed 2024)

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