Being identified as “PD-L1 positive” means that a patient’s cancer cells, or the immune cells surrounding the tumor, are expressing a protein called Programmed Death-Ligand 1 (PD-L1). PD-L1 is the binding partner to Programmed Death-1 (PD-1), which is found on the surface of immune T-cells, the body’s specialized fighter cells. This protein acts as a biomarker, indicating the tumor is attempting to hide from the body’s natural defense system. The presence of PD-L1 is not a diagnosis in itself, but rather a finding that guides treatment decisions for certain types of cancer.
The Biological Mechanism of Immune Evasion
The interaction between PD-1 and PD-L1 is a natural “off-switch” within the immune system, designed to maintain balance and prevent T-cells from attacking healthy tissues (autoimmunity). When PD-L1 connects with PD-1, it sends a signal to the T-cell to stop its activity, essentially putting a brake on the immune response. Cancer cells exploit this normal biological pathway to survive and grow undetected.
The immune system often recognizes tumors as threats, launching an attack using activated T-cells. In response, cancer cells increase the display of PD-L1 on their surface to evade destruction. When T-cells attempt to engage, the cancer cell’s PD-L1 binds to the T-cell’s PD-1, deactivating the immune cell before it can kill the tumor cell. This mechanism allows the cancer to suppress the local immune response, promoting tumor growth.
Measuring PD-L1 Status and Scoring Systems
The determination of a tumor’s PD-L1 status is a precise clinical process performed on a tumor tissue sample, typically obtained through a biopsy. Pathologists use immunohistochemistry (IHC), applying a specific antibody that binds to the PD-L1 protein, revealing its presence with a visible stain. The final result is expressed as a score quantifying the amount of PD-L1 expression. Two primary scoring systems interpret the IHC results, depending on the cancer type and the drug considered for treatment.
Tumor Proportion Score (TPS)
The TPS measures the percentage of viable tumor cells showing PD-L1 staining on their membrane. For example, a TPS of 50% means half of the tumor cells are expressing PD-L1.
Combined Positive Score (CPS)
The CPS is a more comprehensive measurement that accounts for PD-L1 expression on tumor cells and surrounding immune cells (e.g., lymphocytes and macrophages). This score is calculated by dividing the total number of PD-L1-positive cells (tumor and immune cells) by the total number of viable tumor cells, then multiplying by 100. Because the denominator is only the tumor cells, the CPS result can sometimes exceed 100. Both TPS and CPS rely on specific cutoff percentages (such as 1% or 50%) defined by clinical trials to determine eligibility for particular therapies.
Treatment Implications for PD-L1 Positive Cancers
PD-L1 positivity serves as a predictive biomarker used to estimate the likelihood that a patient will benefit from a specific treatment. This status guides the use of immune checkpoint inhibitors, such as pembrolizumab and nivolumab. These monoclonal antibodies are designed to interrupt the PD-1/PD-L1 interaction. This therapeutic approach has significantly changed the treatment landscape for many advanced cancers, often leading to durable responses.
The drugs work by physically blocking the PD-1 protein on the T-cell or the PD-L1 protein on the cancer cell, preventing them from binding. By blocking this inhibitory signal, the drugs “release the brakes” on the T-cells, allowing them to reactivate and destroy the cancer cell.
PD-L1 status is important in several cancer types:
- Non-small cell lung cancer
- Melanoma
- Head and neck squamous cell carcinoma
- Bladder cancer
For example, in non-small cell lung cancer, a high TPS score (50% or greater) indicates a higher probability of response to PD-1/PD-L1 inhibitors as a first-line treatment. Immunotherapy may also be an option for cancers with a lower PD-L1 score, often used in combination with chemotherapy. While a higher PD-L1 score generally correlates with a greater chance of response, it is not a perfect indicator. Some patients with high expression may not respond, and others with low or no detectable PD-L1 expression still benefit from the therapy.
Clinical Nuance and Variability in Test Results
The result of a PD-L1 test is not a fixed metric. PD-L1 expression can be dynamic, changing over time due to factors such as prior treatments, including chemotherapy or radiation. Chemotherapy can sometimes induce an increase in PD-L1 expression, potentially making the tumor more susceptible to subsequent immunotherapy.
Expression can also vary significantly within different areas of the same tumor or between a primary tumor and its metastatic sites, a phenomenon known as tumor heterogeneity. Consequently, a low PD-L1 score does not automatically exclude a patient from receiving immunotherapy, especially when other clinical factors suggest a potential benefit.
PD-L1 status is part of a broader assessment of the tumor’s microenvironment, which is often described as “hot” or “cold.” A “hot” tumor has many immune cells infiltrating it, suggesting an active immune response, while a “cold” tumor has few T-cells. PD-L1 expression often occurs in “hot” tumors as the cancer’s adaptive defense against the ongoing immune attack.