NKG2A inhibitory receptor (NKG2A)

The NKG2A inhibitory receptor, also known as KLRC1, is a key immune checkpoint protein primarily expressed on Natural Killer (NK) cells and a subset of cytotoxic CD8+ T cells (UniProt: P26715). It functions by forming a heterodimer with CD94 to recognize HLA-E, a non-classical MHC class I molecule that presents leader sequence peptides from other HLA molecules, serving as a marker of cellular health (PubMed: 9486650). In many cancers, HLA-E is upregulated as an immune evasion mechanism; when it binds to NKG2A, it triggers an inhibitory signal via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that suppresses the effector functions of the immune cells (PubMed: 30504698). This interaction is a significant barrier in adoptive cell therapies, such as those using donor memory-like NK cells, where tumor-expressed HLA-E can shut down the anti-tumor activity of the infused cells (PubMed: 33024321). Therapeutic strategies, most notably the monoclonal antibody monalizumab, aim to block the HLA-E/NKG2A axis to restore and enhance the cytotoxic potential of NK cells and T cells against tumors (PubMed: 30504698). This target is currently being investigated in clinical trials for various malignancies, including head and neck squamous cell carcinoma and colorectal cancer (ClinicalTrials.gov).

Other names

KLRC1CD159aKiller cell lectin-like receptor subfamily C member 1NKG2A/CD94 complexHLA-E receptor

Immune checkpoint inhibition by blocking the interaction between the NKG2A receptor on immune cells and its ligand HLA-E on target cells, thereby preventing inhibitory signaling and enhancing effector cell cytotoxicity.