PD-L1 Pathway Biomarker

Cancer cells use various strategies to survive in the body. One strategy cancer cells use to survive is immune system evasion or their ability to hide from the immune system (specifically, T-cells). Normally, the immune system works to detect and remove threats, like abnormal or mutated cells, using “checkpoints.” These “checkpoints” are proteins that act like an on/off switch to control the immune system response. Cancer cells can only survive when they are able to avoid being attacked and killed by the immune system, often by overriding these “checkpoints.”

Some cancer cells can express PD-L1 (programmed cell death protein 1 ligand) as a mechanism to evade the immune system. The cancer cells expressing PD-L1 can “trick” T-cells (expressing the “checkpoint” protein PD-1) into thinking they are healthy cells. When PD-1 on T-cells binds to PD-L1 on cancer cells, the T-cells are instructed to leave the cancer cells alone.

It may be helpful to think of T-cells as security guards. While PD-L1 acts as a disguise to hide cancer cells. Normally T-cells, or the security guards, should remove all cancer cells. Unfortunately, cancer cells expressing PD-L1 (the disguise) “trick” the T-cells into letting them stay.

Immunotherapy is a type of treatment used to treat colorectal cancer. Immune checkpoint inhibitors are a type of immunotherapy used in treatment. PD-1 or PD-L1 inhibitors, one type of immune checkpoint inhibitors, block the binding of PD-L1 to PD-1. As a result, the immune system response is boosted, which allows the immune system (specifically, T-cells) to identify, attack, and kill cancer cells.

Cancer cells with high levels of PD-L1 can evade or hide from the immune system. Therefore, PD-L1 can serve as a prognostic biomarker that can help determine the behavior of cancer cells.

There are currently no recommendations for PD-L1 testing in colorectal cancer. However, there are ongoing efforts to understand the potential for PD-L1 to serve as a clinical biomarker in colorectal cancer.

Pembrolizumab and nivolumab are FDA-approved PD-1 inhibitors used to treat patients with MSI-H/dMMR metastatic colorectal cancer. While pembrolizumab can be used as a first line treatment for patients with MSI-H/dMMR metastatic colorectal cancer, nivolumab is often used as a second line treatment for patients with metastatic colorectal cancer that progressed after treatment with chemotherapies. Nivolumab may be used alone or in combination with ipilimumab.

Ipilimumab is another immune checkpoint inhibitor. However, this treatment inhibits a different protein (CTLA-4) that is expressed on T-cells.

Use of PD-1 and PD-L1 inhibitors, as well as other immune checkpoint inhibitors, for treating both MSI-H and MSS colorectal cancers are being tested in clinical trials. As only a small percentage of metastatic colorectal cancers are MSI-H, there is ongoing research and clinical trials surrounding the potential use of immunotherapies in MSS metastatic colorectal cancers. Talk to your medical team to determine if you may benefit from a clinical trial.

Check out Fight CRC’s Clinical Trial Finder to search for trials, and read our Clinical Trials Conversations blog for insights on important trials.