The programmed death-ligand 1 (PD-L1) test is a predictive biomarker guiding the use of immune checkpoint inhibitors. The test measures the amount of PD-L1 protein present on the surface of tumor cells and surrounding immune cells. Oncologists use this measurement to determine the likelihood that a patient’s cancer will respond to anti-PD-1 or anti-PD-L1 immunotherapy drugs. A “negative” result suggests a lower chance of success with single-agent immunotherapy, but it does not mean treatment is impossible or that the prognosis is poor.
Understanding PD-L1 and Immune Evasion
The PD-L1 protein helps maintain immune balance by preventing T-cells from attacking healthy tissues. PD-L1 acts as a molecular “off switch” when it binds to its partner protein, PD-1, which is found on the surface of T-cells. This interaction suppresses the T-cell’s activity, telling it not to attack the cell it is engaging with.
Cancer cells hijack this natural regulatory system to protect themselves. By displaying high levels of PD-L1, tumor cells engage PD-1 receptors on infiltrating T-cells, effectively putting them to sleep. This process, known as immune evasion, allows malignant cells to escape destruction by the body’s defenses. Checkpoint inhibitor drugs work by blocking the PD-1/PD-L1 interaction, releasing the T-cells’ brakes and allowing them to attack the tumor.
Interpreting a PD-L1 Negative Result
A PD-L1 negative result means the cancer is not primarily using the PD-L1 pathway to shield itself from the immune system. This finding translates to a low probability of the tumor responding to a single-agent PD-1 or PD-L1 inhibitor drug. For many cancer types, a negative result indicates that standard first-line immunotherapy monotherapy is not the most effective option.
The negative result suggests that T-cells infiltrating the tumor are not activated or are not present in high numbers. Consequently, the cancer cells have not been prompted to express PD-L1 as a defense mechanism. The absence of PD-L1 expression means there is no target for the single-agent immunotherapy drug to block. The test’s predictive value is highest in cases with very high PD-L1 expression, where the chance of response is significantly greater.
Patients with little to no PD-L1 expression may still respond to monotherapy, but the rates are substantially lower. Therefore, a negative result shifts the treatment strategy away from single-agent immunotherapy toward established or combination approaches. This result indicates which specific therapeutic path is least likely to succeed alone, rather than defining the overall prognosis.
Treatment Pathways When PD-L1 is Negative
A PD-L1 negative result directs the treatment plan toward other proven modalities. Traditional systemic treatments, such as chemotherapy, remain highly effective and are often the preferred first-line option for PD-L1 negative tumors. Chemotherapy rapidly reduces the tumor burden and has an immunomodulatory effect, potentially making the tumor more susceptible to immunotherapy later.
For many cancer types, the most common strategy for PD-L1 negative disease is a combination of chemotherapy and immunotherapy. Studies, particularly in non-small cell lung cancer, show that combining a checkpoint inhibitor with chemotherapy offers better outcomes than chemotherapy alone, regardless of PD-L1 status. Chemotherapy can induce immunogenic cell death, releasing tumor antigens and increasing T-cell infiltration, which may reverse the PD-L1 negative state.
Another effective alternative is dual checkpoint blockade, combining an anti-PD-1 or anti-PD-L1 agent with a drug targeting a different immune checkpoint, such as anti-CTLA-4. This combination therapy benefits PD-L1 negative tumors because the CTLA-4 blocker helps activate T-cells in the lymph nodes. These activated T-cells are driven into the tumor, where the PD-1/PD-L1 blocker prevents their suppression. Targeted therapies are also available if the tumor harbors specific genetic mutations, offering another effective, non-immunotherapy pathway.
The Nuances of PD-L1 Testing
Interpreting a PD-L1 negative result is complicated by the inherent variability and limitations of the testing process. PD-L1 expression is not static; it can change over time and differ between the primary tumor and metastatic sites. This variation, known as tumor heterogeneity, means the small biopsy sample taken for testing may not accurately represent the entire tumor’s PD-L1 status, potentially leading to a false negative result.
The testing methodology is complex because different drug manufacturers developed specific companion diagnostic assays. Each assay uses a unique antibody clone (such as 22C3, 28-8, SP142, or SP263). These assays are often not perfectly interchangeable and use different cutoff scores to define “positive” or “negative” for a specific drug and cancer type. For instance, a tumor may be classified as negative using a 1% cutoff, but positive if a different scoring system is applied.
Different scoring metrics are used to calculate the result. These include the Tumor Proportion Score (TPS), which counts only PD-L1 on tumor cells, and the Combined Positive Score (CPS), which includes PD-L1 expression on both tumor cells and tumor-infiltrating immune cells. This reliance on different, non-standardized assays and scoring systems adds a layer of technical nuance. Therefore, a negative result must be considered within the context of the specific test performed and the particular cancer diagnosis.