Status of NKG2A-targeting drugs under research—PART I

NKG2A (NK cell lectin-like receptor subfamily C member 1)
Molecular Alias: NKG2A ( https://www.creative-biolabs.com/magic-antibody-discovery-human-nkg2a-cd... ), CD159a, KLRC1, NK cell receptor A

Background:NKG2A/B/C/D/E/F are members of the natural killer cell receptor family2 (NKG2). NKG2A, also known as killer cell lectin like receptor C1 (KLRC1), CD159a, and NK cell receptor A, is an inhibitory receptor of the NKG2 receptor family. It's one of the transmembrane proteins that NK cells preferentially express on their surfaces. NKG2A is mainly expressed on the surface of NK cells and in some T cells (CD8+ T cells, Th2 cells, and NKT cells). NKG2A forms a heterodimeric complex with CD94 molecules (NK cell surface membrane proteins) on the surface of human immune cells in the form of disulfide-linked NKG2A-CD94, which is recognized on target cells by the non-classical major histocompatibility complex class I (MHC I) component HLA-E, a molecule that is ordinarily under-expressed, but its expression increases on the surface of most tumor cells, producing a cascade of inhibitory signals that block NK cytotoxicity and cytokine release. This pathway allows certain viral infections, malignancies, and immunological disorders to avoid immune investigation.

Expression:NKG2A is found in several tissues of the body, with peripheral blood cells expressing the most, followed by bone marrow and lymphocytes. NK cells express the most NKG2A (about 50%) among peripheral blood cells, but less than intratumoral NK cells. NKG2A is also expressed on a subset of T cells, primarily CD8+ T cells, Th2 cells, and NKT cells. Surprisingly, the tumor microenvironment appears to play a big role in NKG2A expression on CD8+ T cells. NKG2A expression is modest in CD8+ T cells from the peripheral blood, whereas NKG2A is expressed in significant quantities by the bulk of CD8+ T cells within the tumor. These T cells have a late effector memory phenotype because they lack central memory markers (CCR7, CD27, CD28) and late effector markers (KLRG1) on their surface.

NKG2A ligand—HLA-EThe heterodimeric receptor CD 94/NKG2A, a non-classical MHC class Ib protein, has just HLA-E as a ligand. HLA-E is expressed at low levels in all tissue cells, despite its widespread expression. In cancer cells, however, it is increased, which could be linked to cell-mediated transcription in the tumor microenvironment. T cells and NK cells create interferon gamma in the tumor microenvironment, which upregulates HLA-E transcriptional translation.

NKG2A and disease treatment

TumorIt was discovered that a variety of tumor cells express HLA-E, and that NK and CD8+ T cells in tumor infiltration express NKG2A, allowing tumor cells to elude immunological detection by NK and CD8+ T cells, enabling tumor cells to evade immune recognition by NK and CD8+ T cells. NKG2C inhibitors are now largely employed for tumor treatment since HLA-E is abundantly expressed on the surface of normal cells and is also the ligand of the activating receptor NKG2C.

Viral infectionsIn order to elude immune system clearance, viral infection causes host cells to produce ligands that bind to NKG2A inhibitory receptors on NK and CD8+ T cells. NKG2A is also closely related to SARS-CoV-2. The number of CD8+ T and NK cells in COVID-19 patients was found to be significantly lower than in healthy people, but the expression of NKG2A on the surface of both cells was elevated, whereas the number of NK and CD8+ T cells in the body increased to normal levels after recovery, and the expression of NKG2A was significantly lower. As a result, treating COVID-19 with NKG2A inhibitors in combination with other powerful medications is a viable strategy.