The immune system constantly works to protect the body from foreign invaders and abnormal cells. The Programmed Cell Death Protein 1 (PD1) pathway is a communication system that plays a significant role in regulating immune responses. This pathway helps maintain the body’s immune balance, which can be disrupted by diseases like cancer.
Normal Function of the PD1 Pathway
The PD1 pathway functions as a natural “immune checkpoint,” regulating the strength and duration of immune responses. This prevents the immune system from overreacting and attacking healthy tissues, a process called self-tolerance. The pathway involves a receptor protein called PD-1, found on the surface of activated immune cells, particularly T-cells.
PD-1 interacts with two main ligands: Programmed Death-Ligand 1 (PD-L1) and Programmed Death-Ligand 2 (PD-L2). PD-L1 is widely expressed on various cell types, including antigen-presenting cells (APCs). PD-L2 has a more restricted expression, primarily found on dendritic cells and macrophages.
When PD-1 on a T-cell binds to PD-L1 or PD-L2 on another cell, it delivers an inhibitory signal. This signal dampens the T-cell’s activity, reducing its ability to proliferate, produce inflammatory molecules, and kill target cells. This interaction prevents excessive inflammation and autoimmune reactions.
Cancer’s Exploitation of the PD1 Pathway
Cancer cells have developed strategies to evade the immune system by hijacking its regulatory mechanisms. They achieve this by exploiting the PD1 pathway, creating an immunosuppressive environment.
Many cancer cells frequently overexpress PD-L1 on their surface. This overexpression allows tumor cells to bind with PD-1 receptors on activated T-cells at the tumor site. When PD-L1 on the cancer cell binds to PD-1 on the T-cell, it sends the same “stop” signal.
This binding “deactivates” or “exhausts” T-cells, preventing them from recognizing and eliminating cancer cells. T-cells become inhibited in the tumor microenvironment, losing their ability to proliferate, produce anti-tumor cytokines, and execute cytotoxic functions. This mechanism allows cancer cells to escape immune surveillance and grow and spread unchecked.
Targeting the PD1 Pathway in Cancer Treatment
The discovery of cancer’s exploitation of the PD1 pathway paved the way for a new class of cancer treatments known as immune checkpoint inhibitors. These therapies aim to “release the brakes” on the immune system, allowing T-cells to regain their ability to fight cancer.
These treatments involve specific monoclonal antibodies designed to block the interaction between PD-1 and its ligands. For instance, drugs like pembrolizumab and nivolumab are anti-PD-1 antibodies. Other drugs, such as atezolizumab, durvalumab, and avelumab, are anti-PD-L1 antibodies, which bind to the PD-L1 ligand on cancer cells or antigen-presenting cells.
By blocking either PD-1 or PD-L1, these antibodies prevent the inhibitory signal from being transmitted to the T-cells. This blockade reactivates the T-cells, allowing them to recognize the cancer cells as foreign and mount an effective anti-tumor immune response. The T-cells are then able to proliferate, infiltrate the tumor, and release cytotoxins that induce programmed cell death in the cancer cells. This approach represents a significant advancement in cancer therapy by harnessing the body’s own immune system to combat the disease.
Applications and Considerations of PD1 Pathway Blockade
PD1 pathway blockade therapies have transformed the landscape of cancer treatment, demonstrating remarkable success in various malignancies. These therapies have achieved significant clinical benefits in cancers such as melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, and Hodgkin lymphoma. For example, melanoma, often characterized by a high tumor mutation burden, has shown a notable response to anti-PD-1 therapy due to the increased visibility of mutated cancer cells to the reactivated immune system.
Despite their successes, these therapies are not universally effective for all patients or all cancer types. The response rate can vary, with some patients not responding at all or developing resistance over time. This variability can be due to factors like the cancer cells adapting to survive without relying as heavily on the PD1 pathway or the patient’s immune system becoming exhausted.
Treatment with PD1 pathway inhibitors can lead to immune-related adverse events (irAEs) because the activated immune system can sometimes target healthy tissues. Common side effects include skin rashes, itching, and gastrointestinal issues like diarrhea. Endocrine problems, such as hypothyroidism or hyperthyroidism, and lung inflammation (pneumonitis) can also occur. While less frequent, neurological disorders and myocarditis are rare but potentially severe side effects. These side effects are typically managed with immunosuppressive medications, such as corticosteroids, to control the inflammation while preserving the anti-tumor immune response.