PD-L1: A Stomach Cancer Biomarker

A biomarker refers to any biological characteristic found in your tissues or bodily fluids that can be measured and evaluated objectively. Examples of biomarkers used in clinical practice include your blood pressure and heart rate.

Biomarkers serve as indicators of normal or abnormal processes, conditions, or diseases such as cancer. In oncology, biomarkers can come in the form of proteins, nucleic acids (DNA and RNA) and many other biological molecules derived from your blood, urine, saliva, and tumor tissues.

These biomarkers are typically involved in cancer formation or are released due to the presence of the disease. Therefore, testing for cancer biomarkers in your blood or tissue samples can reveal important details about the cancer you’ve been diagnosed with.

Programmed death ligand 1 (PD-L1) is a protein found on certain healthy cells in your body. In normal circumstances, it functions as a ‘brake’ to prevent cells in your immune system, called T cells or T lymphocytes, from attacking other normal and healthy cells. This works through PD-L1’s interaction with its partner molecule, programmed cell death protein (PD-1) which are expressed on the surface of the T cells.

Immune checkpoint proteins such as PD-1 are responsible for regulating your body’s immune response. This is achieved when PD-1 binds to PD-L1, which sends an ‘off’ signal to the T cells and prevents the healthy cells from being attacked.

Some cancers are able to avoid detection and attack from your body’s immune system by exploiting these immune checkpoint proteins. For instance, a cancer cell can upregulate the expression of PD-L1 on the surface of the cell where it is able to bind to the PD-1 receptor found on the surface of T cells. This binding triggers an inhibitory signal to the T cells and hence, suppresses your body’s immune response towards the cancer cells, allowing them to evade attack.

Different types of cancers have been shown to express high levels of PD-L1 and immunotherapies targeting the PD-1/PD-L1 pathway have become one of the standard approaches for patients with advanced disease. Emerging evidence has also highlighted an association of high PD-L1 expression with high microsatellite instability (MSI-H) in gastric cancer patients. As such, PD-L1 expression and microsatellite instability (MSI) have been approved as predictive biomarkers for immunotherapy in gastrointestinal malignancies.

Determining PD-L1 levels in gastric cancers

Healthcare professionals measure the amount of PD-L1 in the tumor sample by staining for PD-L1 on the surface of the cells and quantifying it with a scoring system called the PD-L1 combined positive score (CPS). A greater CPS correlates with higher PD-L1 expression found in the tumor and surrounding immune cells. The CPS is then categorized into the following intervals to help oncologists identify patients who might benefit from immunotherapy:

• CPS < 1: No immunotherapy recommended.
• 1 ≤ CPS < 5: No immunotherapy recommended.
• 5 ≤ CPS < 10: Available immunotherapy recommendations.
• CPS ≥ 10: Available immunotherapy recommendations.

However, the cut-off for CPS scores and the relative therapeutic recommendations are subjected to changes and can vary from one immunotherapy drug to another.

Targeting PD-L1/PD-1 for cancer treatment

Both PD-L1 and PD-1 have been increasingly studied as potential targets for cancer treatment since disrupting the interaction between these two proteins would allow T lymphocytes to attack the gastric cancer cells. To this end, scientists have developed immunotherapy drugs called immune checkpoint inhibitors (ICIs), which target checkpoint proteins to trigger an immune response.

Nivolumab and pembrolizumab are two of such ICIs that are widely used to target various types of cancer. They work by binding to PD-1 receptors found on the surface of T cells which prevents its interaction with PD-L1 expressed on the surface of gastric cancer cells. This enables the T cells to kill the cancer cells, thereby shrinking the tumor or slow down disease progression.

If biomarker testing reveals that your gastric tumor has high levels of PD-L1 (CPS ≥ 5) and/or MSI-H, you may be a suitable candidate for immunotherapy. Currently, nivolumab or pembrolizumab used in conjunction with chemotherapy has been approved for use in advanced or metastatic gastric cancers.

PD-L1 as a biomarker in gastric cancer

Studies have shown that PD-L1 is found to be expressed in 57% of gastric cancer cases. Research also further showed that individuals whose tumor have high levels of PD-L1 expression were more likely to respond to monotherapy using ICIs (e.g., nivolumab alone) or combination therapy of nivolumab or pembrolizumab with chemotherapy and were more likely to have improved survival outcomes.

Therefore, PD-L1 has been widely used as a predictive and prognostic biomarker for immunotherapy in gastric cancer. It is standard procedure for tissue biopsies from people with advanced or metastatic gastric cancer to be tested for PD-L1 expression. This allows clinicians to identify people who will benefit from immunotherapy and provide tailored treatment plans, which can improve their chances of survival.