T cells are a specialized type of white blood cell, or lymphocyte, integral to the adaptive immune system’s targeted response against threats. The surface of each T cell is covered with unique T-cell receptors (TCRs) that recognize and bind to specific fragments of antigens from pathogens or abnormal cells. Understanding the regulation of this process has opened new avenues for developing modern cancer therapies.
The Function of T Cells
T cells originate in the bone marrow and mature in the thymus. During maturation, they develop their unique T-cell receptors, which ensures the immune response is precisely targeted to avoid damaging the body’s own tissues. Once mature, these cells circulate throughout the body, patrolling for signs of infection or cellular abnormalities.
The immune system has different types of T cells, each with distinct jobs:
- Helper T cells (CD4+) act as coordinators, releasing signaling molecules called cytokines to activate other immune cells like B cells and cytotoxic T cells.
- Cytotoxic T cells (CD8+) are the direct attackers that identify and eliminate cells infected with viruses or that have become cancerous by inducing programmed cell death.
- Regulatory T cells suppress the immune response once a threat is neutralized, which maintains immune tolerance and prevents autoimmune diseases.
- Memory T cells provide long-term immunity by “remembering” a specific pathogen, allowing for a faster response upon future exposure.
The PD-1 Immune Checkpoint
T cell activity is controlled by signals, including inhibitory pathways known as immune checkpoints, which prevent an excessive immune response from damaging healthy tissues. One inhibitory pathway involves a protein on the T cell surface called Programmed Death-1 (PD-1).
PD-1 functions as a “brake” on T cell activity. When T cells are activated for a prolonged period, like during a chronic infection or within a tumor environment, they express the PD-1 protein on their surface. This expression is a natural mechanism to wind down the immune response and limit collateral damage.
The partner molecule for PD-1 is Programmed Death-Ligand 1 (PD-L1), a protein found on many healthy cells and other cell types. When the PD-1 receptor on a T cell binds to PD-L1 on another cell, it delivers an inhibitory signal. This interaction prevents the T cell from attacking the other cell.
This signaling cascade dampens T-cell activation, reduces cytokine production, and halts the T cell’s ability to kill its target. This process is how the body maintains self-tolerance and protects its tissues from autoimmune attack.
Cancer’s Evasion Mechanism
Cancer cells can exploit the PD-1/PD-L1 checkpoint to hide from the immune system. They achieve this by producing high levels of the PD-L1 protein on their surface. This allows the tumor cells to engage the PD-1 receptor on T cells that arrive to attack the tumor, co-opting a natural safety mechanism for their own survival.
When a T cell approaches a cancer cell expressing PD-L1, the binding of PD-1 to PD-L1 deactivates the T cell before it can attack. Although the T cell correctly identifies the threat, it is shut down. This allows the cancer cell to escape destruction and continue to multiply.
Continuous stimulation and inhibition in the tumor microenvironment can lead to T-cell exhaustion. Exhausted T cells are not dead, but have a reduced capacity to produce cytokines and kill target cells. The presence of exhausted T cells within a tumor is associated with a poorer prognosis.
Targeting the PD-1 Pathway for Treatment
The discovery of this immune evasion method led to the development of cancer drugs known as checkpoint inhibitors. These immunotherapy drugs enable the patient’s own immune system to fight cancer by blocking the PD-1/PD-L1 interaction, effectively releasing the “brakes” on T cells.
These therapies use monoclonal antibodies, which are lab-produced molecules that bind to specific targets. Some drugs are PD-1 inhibitors that bind directly to the PD-1 receptor on T cells. By blocking the receptor, the drug prevents PD-L1 on cancer cells from engaging with it and sending an inhibitory signal.
Other drugs are PD-L1 inhibitors that bind to the PD-L1 protein on tumor cells. This also prevents the interaction with the PD-1 receptor on T cells. In both approaches, blocking the inhibitory signal allows T cells to recognize and attack cancer cells.
This approach has been successful in treating cancers like melanoma, non-small cell lung cancer, kidney cancer, and bladder cancer. By restoring T cell function, checkpoint inhibitors can lead to durable responses and long-term remission in some patients. This strategy highlights the potential of using the immune system to combat the disease.