Programmed Death-Ligand 1, or PD-L1, is a protein found on the surface of some cells, including many cancer cells. It plays a significant role in the immune system’s regulation, influencing how immune cells, particularly T cells, interact with other cells. The level of PD-L1 expression on tumor cells is an important factor in determining treatment strategies for various cancers. This article explains what “low PD-L1 expression” means and its implications for cancer treatment.
The Role of PD-L1
PD-L1 functions as an immune checkpoint, a natural mechanism that helps prevent the immune system from mistakenly attacking healthy cells. When PD-L1 on a cell binds to its partner protein, PD-1, located on the surface of T cells, it sends a signal that tells the T cell to stand down. This interaction is important for maintaining immune tolerance and preventing autoimmune diseases, where the immune system attacks the body’s own tissues.
However, cancer cells often exploit this natural immune pathway to evade detection and destruction by the immune system. Many tumor cells produce high amounts of PD-L1 on their surface, allowing them to bind to PD-1 on T cells and effectively “switch off” the immune attack. This mechanism enables cancer cells to hide from immune surveillance, grow, and spread without being eliminated by the body’s defenses.
How PD-L1 Expression is Measured
Measuring PD-L1 expression typically begins with obtaining a tissue sample from the tumor, often through a biopsy. This sample is then processed and analyzed in a specialized laboratory. The most common method used to detect and quantify PD-L1 protein is immunohistochemistry (IHC).
During IHC, specific antibodies are applied to the tumor tissue section, which bind to the PD-L1 protein if it is present. A chemical reaction then makes the bound antibodies visible under a microscope, allowing pathologists to identify cells expressing PD-L1. The results are frequently reported as a Tumor Proportion Score (TPS), which is the percentage of viable tumor cells that show partial or complete membrane staining for PD-L1.
Understanding Low PD-L1 Expression
Low PD-L1 expression signifies that cancer cells produce only a small amount of this protein on their surface, or in some cases, none at all. The precise threshold for what constitutes “low” can vary depending on the cancer type and the specific diagnostic test employed, but it frequently refers to a Tumor Proportion Score (TPS) of less than 1% or less than 50%. For instance, in non-small cell lung cancer, a TPS between 1% and 49% is often considered low expression.
This low level of PD-L1 suggests that the tumor may not be heavily relying on the PD-1/PD-L1 pathway to escape immune detection. For immunotherapies that specifically block the interaction between PD-1 and PD-L1 (known as PD-1/PD-L1 inhibitors) when used as a single treatment, low PD-L1 expression generally indicates a lower likelihood of the tumor responding. This is because the “brake” that these drugs are designed to release is not a primary mechanism of immune evasion for these particular tumors. While a low PD-L1 level suggests a reduced probability of response to single-agent PD-1/PD-L1 inhibitors, it does not mean that a response is impossible. It guides oncologists toward different or additional therapeutic strategies.
Treatment Approaches When PD-L1 is Low
When a tumor exhibits low PD-L1 expression, a range of alternative or complementary treatment strategies are considered. Low PD-L1 does not mean a lack of treatment options; therapy decisions are personalized. One approach involves combining PD-1/PD-L1 inhibitors with other types of immune checkpoint inhibitors, such as CTLA-4 inhibitors, to activate the immune system through multiple pathways. This combination can potentially overcome the tumor’s ability to evade immune recognition even with low PD-L1.
Chemotherapy is a primary treatment option for many cancers with low PD-L1 expression, as it directly targets cancer cells. In some cases, chemotherapy can also be combined with immunotherapy, which has shown benefit even in patients with low PD-L1 expression. If the cancer has specific genetic mutations, targeted therapies may be an option, as these drugs are designed to interfere with particular molecules driving cancer growth. Clinical trials also offer access to novel treatments and combinations. Treatment decisions are individualized, made in consultation with the oncology team, considering cancer type, stage, and overall health.