NKG2A will be the next PD-L1?

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Mar 01, 2019

In recent times, two research articles on the same immune checkpoint and a cutting-edge review article were published in the journal Cell. The target, NKG2A, has been refocused on, and some researchers speculate that NKG2A may become the next PD-L1.

The other name of NKG2A is KLRC1, which is called killer cell lectin like receptor C1. There are two small names, NKG2 and CD159A, which belong to the CD94/NKG2 natural killer cell lectin receptor family, and there are six other members: NKG2B, NKG2C, NKG2D, NKG2E, NKG2F and NKG2H. They are mainly expressed on the surface of NK cells and CD8+ T cell subsets and are a class of transmembrane proteins present in the type II membrane and the C-type lectin domain.

The NKG2 family can form a complex with KLRD1/CD94 and is involved in the recognition of MHC class I HLA-E molecules in NK cells. The NKG2 family can stimulate or inhibit the cytotoxic activity of NK cells, and therefore is classified into an activating receptor and an inhibitory receptor according to its function, wherein NKG2A and NKG2B are inhibitory receptors, and several others are activating receptors.

The principle of immunotherapy for cancer is relatively easy to understand. It is well known that T cells are the "main force" in the human body to attack cancer cells, but there are some inhibitory receptors on T cells, which inhibit the activity of T cells. This property is also detected by cancer cells and secretes substances that bind to these receptors, leaving T cells inactive, like "brakes." Immunotherapy is to lift these "bindings" and let T cells recover their ability to attack cancer cells.

Immunotherapy can make the immune system "memorize" cancer, and achieve long-term therapeutic effects. For example, some patients have not cancer cell progression for ten years after receiving treatment, which is in line with the clinical "cure". But according to statistics, only about 20% of patients can get long-term benefits from immunotherapy. For most patients, the effect is not significant. Therefore, the continuous development of new immunotherapies is a challenge for many scientists and new drug developers.

The new immunotherapy has paid for with the report of Cell.
NKG2A monoclonal antibody is a detection point inhibitor that promotes anti-tumor immunity by releasing T cells and NK cells. As we wrote above, NKG2A, as a receptor molecule, can be expressed in large amounts on the surface of NK cells and T cells. When bound to a ligand, it inhibits the function of T cells and NK cells, similar to the brakes of immune cells. ". Then, if the binding of NKG2A to the ligand is inhibited, it is possible to restore the immune function of T cells and NK cells, just like PD-L1. Under this idea, researchers conducted in vitro experiments. The results showed that the NKG2A antibody or the PD-L1 antibody alone can increase the activity of immune cells. When used together, it can achieve significantly better results.

The researchers tested the mouse model and found that the NKG2A antibody alone did not have any effect, and the survival rate of the mice was similar to that of the control group. The use of PD-L1 alone can save about 40% of the lives of mice. Unexpected results showed that when NKG2A antibody was used in combination with PD-L1 antibody, this number increased from 40% to 75%, indicating that NKG2A antibody is better than classic tumor immunotherapy.

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