NKG2A Immune Checkpoint Molecule for Drug Development

Immune Checkpoint NKG2A

Natural killer group protein 2A (NKG2A) is a cell surface receptor and member of the NKG2 family that can form a heterodimer with CD94 on the cell surface, also known as KLRD1, another NK cell-expressed C-type lectin. The non-classical MHC class I molecule HLA-E is the major ligand of NKG2A-CD94. These inhibitory receptors interact with MHC I ligands on target cells, leading to complete inhibition of NK cell granule polarization and cytotoxic granule release prevention.

Table.1 Immune checkpoint NKG2A.

Checkpoint receptor	Cell type affected	Ligand	Function of ligand-receptor interaction	Notes
NKG2A	Both T and NK cells	HLA-E	Inhibition	Targeting this checkpoint inhibits signaling on both cell types and unleashes tumor-specific T cell proliferation, memory and can assist in rendering cancer vaccines more effective.

Structure of NKG2A

NKG2A is a type 2 membrane receptor that bears immunoreceptor tyrosine-based inhibition motif (ITIM) domains in its cytoplasmic tail and forms heterodimers with CD94. These ITIMs are phosphorylated following ligation of the ITIM-bearing receptor and facilitate the recruitment of tyrosine phosphatases, such as SH2 domain-containing phosphatase (SHP)-1 and SHP-2.

Expression of NKG2A

NKG2A is a cell surface molecule, typically expressed cytotoxic lymphocytes, including natural killer (NK) cells, natural killer T (NKT) cells, and subsets of activated CD8⁺ T cells. Approximately half of peripheral blood NK cells express NKG2A, and its expression on NK cells can be upregulated upon stimulation with cytokines, such as interleukin-15 (IL-15). The NKG2A ligand is expressed in many tumors, including lung, colon, pancreas, stomach, head and neck, and liver tumors.

Function of NKG2A

The NKG2A-HLA-E interaction inhibits the activation of NK cells and T cells. This inhibition is dependent on the recruitment of the SHP-1 tyrosine phosphatase to the tyrosine-phosphorylated form of the ITIM in NKG2A. Like other receptor-ligand interactions, the NKG2A-HLA-E immune checkpoint is coopted by cancer cells to evade the immune system. In this context, a high density of NKG2A-CD94⁺ tumor-infiltrating lymphocytes (TILs) correlates with worse survival in patients with cancers.

Fig.1 The NKG2A-HLA-E immune checkpoint. (Creelan, 2019)

Clinical Development of Drugs Targeting NKG2A

NKG2A blockade is a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer. The NKG2A-mediated mechanisms are currently being exploited for developing promising immune-therapeutic strategies to improve the prognosis of solid and blood tumors and to ameliorate the clinical outcome of patients undergone allogeneic hematopoietic stem cell transplantation to treat high-risk hematologic malignancies. Besides, NKG2A blockade, either alone or in combination with other checkpoint inhibitors, shows encouraging anti-tumor responses in a subset of patients with cancers.

Services at Creative Biolabs

Creative Biolabs is a well-recognized expert who supports a broad range of drug development projects for immune checkpoints. Currently, a series of custom services for immune checkpoint NKG2A is available at Creative Biolabs, including but not limited to:

Please do not hesitate to contact us for more detailed information.

Reference

Creelan, B.C.; Antonia, S.J. The NKG2A immune checkpoint-a new direction in cancer immunotherapy. Nature Reviews Clinical Oncology. 2019, 16(5), pp.277-278.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.