NK group 2 member A (NKG2A), also known as killer lectin like receptor c1 (KLRC1) and CD159a, is a ~38 kDa type II transmembrane protein belonging to the C-type lectin superfamily and plays a role in suppression of cytotoxic CD8+ T cell activity and functions as an immune checkpoint (1,2). NKG2A belongs to a group of natural killer (NK) cell inhibitor receptors (IRs) which includes killer immunoglobulin receptors (KIRs), lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), programmed death ligand-1 (PD-1), and T cell immunoglobulin mucin-3 (TIM-3) (1,3). NKG2A is synthesized as a protein of 233 amino acids (aa) with a theoretical molecular weight of 26.3 kDa and is expressed on CD56hi NK cells, NKT cells, and some CD8+ alphabeta T cells (2,4). Together with CD94, NKG2A forms a heterodimer and acts as a receptor for the MHC Class I molecular human leukocyte antigen (HLA)-E (1-3). The NKG2A/CD94 receptor interaction with the HLA-E ligand results in phosphorylation of NKG2A's immunoreceptor tyrosine-based inhibition motifs (ITIMs), causing suppression of activating signals from immunoreceptor tyrosine-based activation motif (ITAM)- containing T cell receptors (TCR) or other activating receptors like NKG2D, via the intracellular phosphatase SHP1 (2,3,5). Overall, cancer cells utilize the NKG2A-HLA-E interaction and signaling to evade immune surveillance by NK cells and T cells (1-3,5-6).
Similar to cytotoxic T lymphocyte associated protein 4 (CTLA-4) and PD-1, NKG2A has become a prominent target for immune checkpoint blockade and cancer immunotherapy (1-3,5-6). Monalizumab is a novel IgG4 monoclonal antibody developed for blocking NKG2A's interaction with HLA-E and has shown promising results in clinical trials (1-3,5-6). In addition to being used as a single agent, it is being studied as a possible combination therapy with other blocking antibodies such as anti-PD-L1 and anti-epidermal growth factor receptor (EGFR) (2,5,6).
1. Alfarra, H., Weir, J., Grieve, S., & Reiman, T. (2020). Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy. Frontiers in immunology, 11, 575609. https://doi.org/10.3389/fimmu.2020.575609
2. Creelan, B. C., & Antonia, S. J. (2019). The NKG2A immune checkpoint - a new direction in cancer immunotherapy. Nature reviews. Clinical oncology, 16(5), 277-278. https://doi.org/10.1038/s41571-019-0182-8
3. Zaghi, E., Calvi, M., Marcenaro, E., Mavilio, D., & Di Vito, C. (2019). Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy. Journal of leukocyte biology, 105(6), 1243-1251. https://doi.org/10.1002/JLB.MR0718-300R
4. Uniprot (P26715)
5. Borst, L., van der Burg, S. H., & van Hall, T. (2020). The NKG2A-HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research, 26(21), 5549-5556. https://doi.org/10.1158/1078-0432.CCR-19-2095
6. Andre, P., Denis, C., Soulas, C., Bourbon-Caillet, C., Lopez, J., Arnoux, T., Blery, M., Bonnafous, C., Gauthier, L., Morel, A., Rossi, B., Remark, R., Breso, V., Bonnet, E., Habif, G., Guia, S., Lalanne, A. I., Hoffmann, C., Lantz, O., Fayette, J., ... Vivier, E. (2018). Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell, 175(7), 1731-1743.e13. https://doi.org/10.1016/j.cell.2018.10.014