A novel checkpoint protein provides a new strategy for cancer immune therapy

A study published in the journal Cell characterized a new checkpoint protein on the immune system cells is active in tumors. And the researchers from an international team of Vanderbilt successfully blocked it in combination with other treatments in a mouse model.

An immune checkpoint is a protective factor in the human immune system, which can prevent the inflammation damage caused by excessive activation of T cells. Tumor cells use the characteristic escape from the surveillance and killing of the human immune system to promote themselves growth by extravagantly expressing immune checkpoints. By suppressing immune checkpoint activity, immune checkpoint inhibitor immunotherapy releases immune "brakes" in the tumor microenvironment, thus reactivating the immune response effect of T cells to the tumor to achieve the anti-tumor effect. Currently, immune checkpoint inhibitor immunotherapy is effective for many cancers.

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Nowadays, available checkpoint inhibitors target one of the checkpoint pathways of the immune system, there are more checkpoint proteins in fact.

The researchers studied national killer (NK) cells in head and neck tumor samples to look for the protein in the surface of these cells, which may explain why NK cells do not function properly. NK cells are important immune cells of the body, which can recognize target cells and kill foreign media. They are not only associated with anti-tumor, anti-virus infections, and immune regulation but also are involved in the occurrence of hypersensitivity and autoimmune diseases.

They used the Vanderbilt Flow Cytometry Shared Resource to classify and characterize surface protein-based immune cells. And then they found that a protein called NKG2A is the only inhibitory receptor which is expressed on NK cells in head and neck tumors. But NKG2A is also expressed in NK cells circulating in the blood and it merely expresses slightly higher in tumors.

However, when observing proteins on cytotoxic (CD8 expression) T cells, the researchers noticed a jump in NKG2A. This was a pleasant surprise because NKG2A is usually associated with NK cells. What caught their attention was the apparent expression of CD8 T cells in tumor samples from the head and neck, rather than in the blood.

Cytotoxic T cells also kill virus-infected cells and cancer cells, but they must first be activated by recognizing specific antigens.

Further, they confirmed that tumor cells express a protein that interacts with NKG2A, called HLA-E, and pointed out that NKG2A inhibits cytotoxic T cell activity in tumors. NKG2A expression in head and neck tumors was associated with poor clinical outcomes.

Using mouse tumor models, the researchers found that blocking NKG2A with monalizumab alone had a minimal therapeutic effect. Monalizumab is an anti-NKG2A antibody therapy developed by a company Innate Pharma in Marseille, France. However, combining monalizumab with a cancer vaccine designed to stimulate an anti-tumor immune response reduces tumor growth and prolongs progression-free survival.

The researchers demonstrated that cancer vaccines stimulate the expression of HLA-E in tumors, suggesting that tumors participate in the NKG2A pathway as a mechanism for adaptive resistance to vaccine therapy-blocking this pathway may improve responses to cancer vaccines.

In a trial of monalizumab combined with cetuximab (an antibody against the EGF receptor) in head and neck cancer patients, researchers at Innate Pharma have found a tumor improvement in 30 percent of patients after a combination of treatments.

These findings make NKG2A potentially the third most successful immunotherapy checkpoint. Researchers are now using cell and animal models to further explore the mechanisms by which cetuximab and monalizumab work together, and how cancer vaccines promote HLA-E expression in tumor cells.