Immunotherapy has redefined cancer treatment by harnessing the body’s own defenses, offering an alternative to traditional methods like chemotherapy and radiation. This revolutionary approach involves manipulating “immune checkpoints,” which act as natural brakes on the immune system. These regulatory pathways prevent T-cells from attacking healthy tissue, maintaining a necessary balance within the body. By releasing these brakes, scientists can re-engage the immune system in the fight against cancer.
The Immune System’s Regulatory Pathway
The Programmed Death-1 (PD-1) pathway is a molecular mechanism for regulating immune activity and maintaining self-tolerance. The PD-1 receptor is a protein expressed primarily on activated T-cells, which identify and destroy abnormal cells. Its binding partner, Programmed Death-Ligand 1 (PD-L1), is found on the surface of many other cell types, including antigen-presenting cells and healthy tissue cells.
The interaction between PD-1 and PD-L1 functions as an inhibitory signal, telling the T-cell to stand down. When PD-L1 binds to PD-1, it delivers a “stop signal” that prevents the T-cell from proliferating or releasing cytotoxic substances. This interaction is a safety mechanism designed to protect the body’s own cells from an overzealous immune response.
This regulatory function is particularly important in preventing autoimmune diseases, where the immune system mistakenly attacks healthy tissues. The PD-1/PD-L1 axis helps ensure that T-cells are only activated at the appropriate time and place, minimizing the possibility of chronic inflammation or tissue damage.
Cancer’s Strategy for Immune Evasion
Cancer cells exploit this natural safety mechanism to shield themselves from immune destruction, a process known as immune evasion. Tumor cells often overexpress the PD-L1 protein on their surface. This overexpression is frequently triggered by inflammatory signals, such as interferon-gamma, released by T-cells attempting to infiltrate the tumor.
When an activated T-cell, expressing the PD-1 receptor, arrives at the tumor site, the abundance of PD-L1 on the cancer cell creates a powerful inhibitory interaction. The binding of tumor PD-L1 to T-cell PD-1 sends a direct signal into the T-cell, neutralizing its ability to kill the cancerous cell. This causes the T-cell to become functionally exhausted or anergic, rendering it incapable of executing its anti-tumor duties.
By hijacking this checkpoint, the tumor cell displays a “don’t attack me” flag, allowing it to survive and proliferate unchecked. Immunotherapy seeks to address this problem, as the immune system is actively prevented from mounting an effective response against the cancer.
Blocking the Pathway for Cancer Treatment
The therapeutic application involves immune checkpoint inhibitors, specialized drugs designed to physically block the PD-1/PD-L1 interaction. These inhibitors are monoclonal antibodies engineered to target one specific protein. By blocking the binding site, these drugs prevent the cancer cell’s “stop signal” from reaching the T-cell.
There are two main types of inhibitors: PD-1 inhibitors and PD-L1 inhibitors. PD-1 inhibitors, such as nivolumab and pembrolizumab, bind directly to the PD-1 receptor on the T-cell. This prevents any PD-L1 molecule from engaging the T-cell’s brake.
PD-L1 inhibitors, like atezolizumab and durvalumab, bind to the PD-L1 protein found on the surface of the tumor cell and other cells within the tumor microenvironment. This approach blocks the ligand, leaving the PD-1 receptor on the T-cell free. Both mechanisms restore the T-cell’s cytotoxic function and reactivate the anti-tumor immune response.
Determining which patients will benefit most is a challenge, leading to the development of predictive biomarkers.
PD-L1 Expression
The level of PD-L1 expression on tumor cells is one of the most widely used biomarkers. Tumors with high expression are often more likely to respond to treatment. However, the correlation is imperfect; some patients with PD-L1-negative tumors still respond, while others with high PD-L1 expression may not.
Tumor Mutational Burden (TMB)
Another biomarker is Tumor Mutational Burden (TMB), which measures the total number of mutations within the cancer cell’s DNA. Tumors with a high TMB tend to create more abnormal proteins, making them more visible to the immune system. High TMB can indicate a greater potential for T-cell activation once the inhibitory PD-1 pathway is blocked.
Managing Treatment Side Effects
The success of checkpoint inhibitors comes with a distinct set of side effects, termed immune-related adverse events (irAEs), which are a direct consequence of releasing the immune system’s natural brake. Since the immune system is broadly reactivated, it can lose its ability to distinguish between cancer cells and healthy cells in other parts of the body. This can result in inflammation and damage to various organs.
The most commonly affected organs include:
- The skin, presenting as rashes or pruritus.
- The gastrointestinal tract, leading to colitis and diarrhea.
- The lungs (pneumonitis).
- Endocrine issues, such as thyroid dysfunction.
These adverse events can appear weeks or even months after treatment has begun.
Management of irAEs is guided by the severity of the reaction, with the primary strategy being the administration of high-dose corticosteroids. Corticosteroids act to broadly dampen the overactive immune response, effectively reapplying a brake to the system. For severe or persistent inflammation, the checkpoint inhibitor therapy may need to be temporarily held or permanently discontinued.