Research Team Discovers New Immune “Checkpoint” Protein

A recent report in the journal Cell showed that a team led by Vanderbilt researchers has found a new “checkpoint” protein on immune system cells in active, malignant tumors. In mouse models, blocking this protein, along with using other treatments, has been an effective approach to treating cancerous cells.

Checkpoint proteins are an important component of the immune system, as they prevent the body from attacking its own normal tissues. As many scientists describe it, they act as the “brakes” when the immune system tries to target cells that don’t need targeting. Unfortunately, cancerous cells have used checkpoint proteins to evade the immune system’s detection; even though cancerous cells are “foreign” to the immune system, checkpoint proteins prevents it from attacking, and cancer thrives.

Researchers have discovered that checkpoint inhibitor drugs can prevent these “brakes” from working so that the immune system can properly attack cancerous cells. These drugs have been successful at treating many cancers, especially skin and lung.

There are currently two different immune system checkpoint pathways that checkpoint inhibitor drugs are focused on. But the Vanderbilt research team, which is internationally-based, states that many other checkpoint proteins do exist.

Michael Korrer, Ph.D. and Young J. Kim, MD, Ph.D, discovered one of these checkpoints while studying immune cells in human head and neck cancers that were extracted during surgery. They were studying natural killer (NK) cells, immune cells responsible for finding and destroying abnormal cells, like those affected by cancer.

The team then noticed that a surface protein called NKG2A had increased expression on the NK cells. The protein was the only receptor to have increased reception, but it was only a little bit higher in tumors. But then they saw that proteins on cytotoxic T-cells showed a significant increase in NKG2A. Like NK cells, cytotoxic T-cells also destroy abnormal cells, but they have to be activated by a particular antigen. Korrer’s later studies revealed that the protein interacting with NKG2A is called HLA-E, and also that NKG2A was reducing the amount of cytotoxic activity in tumors.

Korrer and Kim then decided to touch base with Thorbald van Hall, Ph.D., who has done extensive work with HLA-E, and Innate Pharma, a French drug company that has created an anti-NKG2A antibody called monalizumab.

The combined team looked at mouse tumor models to determine the effects of monalizumab on NKG2A expression. They discovered that that preventing NKG2A expression alone did not have much effect. But when they combined the drug with a cancer vaccine that prompts an immune response, tumor growth was inhibited and survival-time was increased.

Korrer says these preliminary results suggest that “NKG2A-targeted treatments have to be combined with something causing inflammation in the tumor, such as a cancer vaccine.”

This research shows that the anti-cancer vaccine triggered HLA-E expression in the tumor, which means that tumors use the NKG2A pathway as a way to resist vaccine therapy. Thus, closing the pathway might allow cancer vaccines to work more effectively.

Innate Pharma reported that a separate study showed monalizumab in combination with cetuximab, an antibody for the EGC receptor, reduced the tumor burden in 30% of patients.

Researchers are enthusiastic about these preliminary results, as they suggest that NKG2A could be the third most effective immunotherapy checkpoint. Additional studies on the inhibitor therapies and cancer vaccines are currently being done.