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.
Cell type affected
Function of ligand-receptor interaction
Both T and NK cells
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: