The protein Programmed Death-Ligand 1 (PD-L1) is found on the surface of some cancer cells and immune cells, playing a major role in how the immune system interacts with tumors. Testing for the presence and quantity of this protein has become a standard procedure in modern oncology, helping determine the best course of action against a patient’s cancer. While a high PD-L1 result generally suggests that certain immunotherapies will be effective, a low test result presents a more complex clinical picture. Understanding the implications of low PD-L1 expression is essential for navigating treatment options. This article explores the biological implications and resulting strategies used in cancer care.
The Role of PD-L1 in Cancer Immunity
PD-L1 is part of a mechanism known as an immune checkpoint, which serves to maintain a necessary balance between fighting foreign invaders and preventing the immune system from attacking the body’s own healthy cells. This mechanism involves the interaction between PD-L1 and its partner, the PD-1 receptor, which is expressed on the surface of activated T-cells. When PD-L1 binds to PD-1, it delivers an inhibitory signal to the T-cell, acting as an “off switch” that prevents the T-cell from launching an attack.
Cancer cells often exploit this natural biological pathway to evade destruction by the immune system. By overexpressing PD-L1 on their surface, tumor cells shield themselves from T-cell surveillance, a process called immune evasion. Doctors test for PD-L1 expression to determine if the tumor is actively using this “off switch.” Therapies known as immune checkpoint inhibitors are designed to block this interaction, thus “releasing the brakes” on the T-cells and enabling them to attack the tumor.
Interpreting Low PD-L1 Test Results
PD-L1 expression is measured through specific laboratory tests using scoring systems that quantify the percentage of cells showing the protein. One common method is the Tumor Proportion Score (TPS), which calculates the percentage of viable tumor cells that stain positive for PD-L1. Another method is the Combined Positive Score (CPS), which counts PD-L1-staining cells, including tumor cells, lymphocytes, and macrophages, relative to the total number of viable tumor cells.
A low PD-L1 expression result means the tumor is not heavily utilizing the PD-L1/PD-1 pathway to avoid immune detection. For TPS, low expression is often defined as a score between 1% and 49%, while a score below 1% is considered negative. For CPS, the cutoff for low expression can vary but is often in the range of 1 to 19. Clinically, a low score suggests that the tumor microenvironment may be “cold,” meaning there is a low presence of active, tumor-infiltrating immune cells.
The implication of a low score is that the tumor is likely using other, non-PD-L1-related mechanisms to suppress the immune response. For example, some tumors with low PD-L1 expression have developed genetic strategies to avoid the action of gamma interferon, a molecule that normally stimulates a strong immune reaction. PD-L1 testing is an important but imperfect biomarker, as it provides only one piece of information about the complex immune landscape of a tumor.
Treatment Implications for Low PD-L1 Tumors
Low PD-L1 expression is associated with a significantly reduced likelihood of response to single-agent PD-1 or PD-L1 checkpoint inhibitors. If the tumor is not using PD-L1 as its main defense mechanism, blocking it with a drug like pembrolizumab (Keytruda) or nivolumab (Opdivo) is less likely to yield a major clinical benefit. This is referred to as primary resistance to immunotherapy, where the drug’s target is minimally present.
Due to this reduced efficacy, clinical guidelines often restrict the use of these drugs as monotherapy in the first-line setting for patients with low PD-L1 expression. For instance, in non-small cell lung cancer (NSCLC), a PD-L1 TPS of 50% or higher is required for single-agent pembrolizumab to be considered a standard first-line treatment. However, some patients with low or even negative PD-L1 scores still experience a durable benefit from monotherapy, complicating treatment decisions.
A low score redirects the treatment strategy away from single-agent immunotherapy. While the overall response rate is lower in the low-expression group compared to the high-expression group, a subset of patients can still respond. The clinical focus shifts to combining the checkpoint inhibitor with other therapies to overcome the tumor’s immune-evasion strategies.
Alternative Treatment Strategies
For patients with low PD-L1 expression, the standard approach involves combination therapy or traditional cancer treatments. Chemotherapy, often combined with radiation, remains a foundational and effective treatment option. Targeted therapies, which attack specific mutations found within the tumor cells, are also utilized when applicable to the patient’s cancer type.
A common and highly effective strategy for low PD-L1 tumors is combining a checkpoint inhibitor with chemotherapy. Clinical trials show that adding a PD-1 inhibitor like pembrolizumab to platinum-based chemotherapy significantly improves overall survival and progression-free survival compared to chemotherapy alone, even in low PD-L1 patients. Chemotherapy is thought to “heat up” the tumor microenvironment by causing cell death, which releases tumor-specific antigens and makes the cancer more visible to the immune system.
Another approach is dual immunotherapy combinations, such as nivolumab paired with the CTLA-4 inhibitor ipilimumab. CTLA-4 is a different immune checkpoint, and blocking both pathways simultaneously provides a more comprehensive release of the immune system’s brakes. This strategy has shown benefit in PD-L1-negative patients with certain cancers, leveraging the power of immunotherapy even when the PD-L1 biomarker suggests poor success with a single agent.