Immune checkpoint molecules act as natural “brakes” or “regulators” for the body’s immune system, ensuring it functions correctly without overreacting. Their primary role is to prevent the immune system from becoming overly aggressive and attacking healthy tissues. These molecules help maintain overall balance.
What are Immune Checkpoint Molecules?
Immune checkpoint molecules are proteins found on the surface of various immune cells, particularly T-cells. They function by either stimulating or inhibiting immune cell activity, acting like “on” and “off” switches for the immune system. This regulation involves interactions with specific partner proteins, known as ligands, on other cells. The balance between these signals determines whether an immune response is amplified or dampened.
How Immune Checkpoints Maintain Balance
Immune checkpoints are essential for maintaining the body’s immune balance. They prevent the immune system from mistakenly attacking its own healthy cells, a process called self-tolerance. They also help to dampen immune responses once an infection has been cleared, preventing prolonged inflammation and damage to healthy tissues. This allows the immune system to distinguish between “self” and “non-self” elements, protecting the body and enabling it to return to a stable state.
Key Immune Checkpoint Pathways
Two prominent immune checkpoint pathways, CTLA-4 and PD-1/PD-L1, are extensively studied due to their roles in immune regulation and therapeutic potential. CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4) acts as an early brake on T-cell activation. After a T-cell is activated, CTLA-4 is moved to the cell surface, where it competes with a stimulatory molecule called CD28 for binding to proteins known as B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells. CTLA-4’s stronger binding affinity to B7 molecules effectively reduces T-cell activation, proliferation, and the production of signaling molecules, thus dampening the immune response.
The PD-1 (Programmed Cell Death Protein 1) and PD-L1 (Programmed Death-Ligand 1) pathway operates primarily in peripheral tissues during the later stages of an immune response. The PD-1 receptor is found on activated T-cells, while its ligands, PD-L1 and PD-L2, are expressed on various cells, including dendritic cells, macrophages, and often on cancer cells. When PD-1 on a T-cell binds to PD-L1 on another cell, it sends an inhibitory signal that suppresses the T-cell’s activity, preventing it from attacking healthy cells. This interaction is a natural mechanism to prevent excessive immune responses and chronic inflammation.
Immune Checkpoint Inhibitors in Cancer Therapy
Cancer cells frequently exploit immune checkpoint pathways, particularly the PD-1/PD-L1 pathway, to evade detection and destruction by the immune system. These cancer cells can overexpress PD-L1 on their surface, which then binds to PD-1 on T-cells, effectively deactivating the T-cells and allowing the cancer to grow unchecked. Immune checkpoint inhibitors are a type of immunotherapy that work by blocking these specific interactions. These drugs, often monoclonal antibodies, prevent the “off” signal from being sent to the T-cells, thereby “releasing the brakes” on the immune system.
By blocking CTLA-4, PD-1, or PD-L1, these inhibitors allow T-cells to remain active and recognize and attack cancer cells more effectively. For instance, PD-1 inhibitors block the PD-1 receptor on T-cells, while PD-L1 inhibitors target the PD-L1 ligand on cancer cells, both preventing the inhibitory signal. This re-enables the T-cells to carry out their anti-tumor functions, such as releasing cytotoxins that induce cancer cell death.
Immune checkpoint inhibitors have had a transformative impact on cancer treatment, leading to significant improvements in survival for patients with various advanced cancers, including melanoma, non-small cell lung cancer, and bladder cancer. While generally effective, these therapies can cause side effects known as “immune-related adverse events” (irAEs). These side effects result from the immune system becoming overactive and mistakenly attacking healthy tissues, similar to autoimmune conditions. Common irAEs can include rashes, diarrhea, and inflammation in various organs like the liver, lungs, or endocrine glands, although most can be managed with medical intervention.