KLRC1

Official Full Name

killer cell lectin like receptor C1

Organism

Homo sapiens

GeneID

3821

Background

Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor family, also called NKG2 family, which is a group of transmembrane proteins preferentially expressed in NK cells. This family of proteins is characterized by the type II membrane orientation and the presence of a C-type lectin domain. This protein forms a complex with another family member, KLRD1/CD94, and has been implicated in the recognition of the MHC class I HLA-E molecules in NK cells. The genes of NKG2 family members form a killer cell lectin-like receptor gene cluster on chromosome 12. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jan 2015]

Synonyms

NKG2; NKG2A; CD159A;

Protein Sequence

MDNQGVIYSDLNLPPNPKRQQRKPKGNKNSILATEQEITYAELNLQKASQDFQGNDKTYHCKDLPSAPEKLIVGILGIICLILMASVVTIVVIPSTLIQRHNNSSLNTRTQKARHCGHCPEEWITYSNSCYYIGKERRTWEESLLACTSKNSSLLSIDNEEEMKFLSIISPSSWIGVFRNSSHHPWVTMNGLAFKHEIKDSDNAELNCAVLQVNRLKSAQCGSSIIYHCKHKL

Open

Disease

Head and neck cancer, Mature B-cell leukaemia, Rheumatoid arthritis, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

NKG2A, fully named Natural Killer Group 2 Member A, also known as Killer Cell Lectin-Like Receptor C1 (KLRC1), is a member of the NKG2 family and functions as an inhibitory receptor expressed on both T cells and NK cells. In the peripheral blood of patients with chronic viral infections and tumors, over 50% of NK cells and cytotoxic T lymphocytes (CD8+ T cells) express NKG2A on their surface.

Overview of NKG2 receptor family interactions with HLA-E and stress-induced ligands, mediating activating or inhibitory signals in NK and CD8 T cells. Figure 1. NKG2 family and their ligands. (Borst L, et al., 2020)

NKG2A Expression and Mechanism of Action

NKG2A is primarily expressed on NK cell surfaces and certain T cells (CD8+ T cells, Th2 cells, and NKT cells). NKG2A can be expressed in multiple organs and tissues of the human body, with the highest expression in peripheral blood cells, followed by bone marrow and lymphocytes. Among peripheral blood cells, NK cells express the highest level of NKG2A (approximately half), though this is lower than the expression level in tumor-infiltrating NK cells.

On the surface of human immune cells, NKG2A forms a heterodimeric complex with the CD94 molecule (an NK cell surface membrane protein) connected by disulfide bonds, forming the NKG2A-CD94 complex. This complex is recognized by HLA-E, a non-classical major histocompatibility complex class I (MHC I) molecule on target cells. HLA-E is normally expressed at low levels, but its expression is elevated on the surface of most tumor cells, which induces cascading inhibitory signals, suppressing NK cell cytotoxicity and cytokine secretion.

In humans, NKG2A binds to human leukocyte antigen E (HLA-E), and the relationship between NKG2A and HLA-E is similar to that of PD-1 and PD-L1. This makes NKG2A a promising immune checkpoint, with NKG2A inhibitors potentially enhancing the anti-tumor capabilities of T cells and NK cells.

NKG2A and Disease Relationships

Research has found that various tumor cells highly express HLA-E, and tumor-infiltrating NK and CD8+ T cells highly express NKG2A, allowing tumor cells to evade immune recognition by NK and CD8+ T cells. Since HLA-E is widely expressed on normal cell surfaces and is also a ligand for the activating receptor NKG2C, NKG2C inhibitors are now commonly used for tumor treatment.

After viral infection, host cells can be induced to express ligands that bind to the inhibitory NKG2A receptor on NK and CD8+ T cells, evading immune system clearance. Studies have found that COVID-19 patients have significantly lower numbers of CD8+ T and NK cells compared to healthy individuals, but both cell types show increased NKG2A expression. After recovery, the number of NK and CD8+ T cells in the body increases to normal values, and NKG2A expression decreases significantly. Therefore, using NKG2A inhibitors in combination with other specific drugs is a viable treatment option for COVID-19.

The expression of NKG2A is generally downregulated in patients with autoimmune diseases. NK cells in the knee joint synovial fluid of rheumatoid arthritis patients highly express the NKG2A-CD94 receptor; circulating NK cells in psoriasis patients show downregulated NKG2A; and T cells in the peripheral blood of systemic lupus erythematosus patients have downregulated NKG2A.

Clinical Applications of NKG2A Antibodies

Monalizumab, co-developed by Innate Pharma and AstraZeneca, is a monoclonal antibody against NKG2A that blocks the interaction between NKG2A and HLA-E. Monalizumab has entered Phase II clinical trials as a treatment for female reproductive system cancers, with intravenous administration of 10 mg/kg every two weeks. Trial results show good therapeutic effects, even achieving short-term disease stabilization.

Monalizumab combined with cetuximab (an EGFR blocking antibody) for treating recurrent or metastatic head and neck squamous cell carcinoma achieved an effectiveness rate of 27.5%, with a median progression-free survival of 5.0 months and a median overall survival of 10.3 months. At the 2018 ESMO conference, AstraZeneca/Innate Pharma announced that the Phase II clinical trial of Monalizumab+cetuximab in recurrent or metastatic head and neck squamous cell carcinoma reached a total response rate of 27.5%, without increasing the side effects of cetuximab.

However, over the past two years, Monalizumab's prospects in head and neck cancer treatment have deteriorated. After the failure of its Phase II clinical trial for head and neck cancer treatment in 2021, in August 2022, the INTERLINK-1 Phase III clinical trial of Monalizumab+cetuximab as second-line treatment for head and neck cancer was also terminated due to poor clinical results.

In non-small cell lung cancer, AstraZeneca disclosed Phase II clinical data of PD-L1+Monalizumab combination therapy for NSCLC at AACR 2021, showing that adverse events, PFS, and other metrics were significantly better than PD-L1 therapy alone. Further data research in April 2022 showed that durvalumab+Monalizumab achieved an objective response rate (ORR) of 35.55% and a one-year progression-free survival rate of 72.7%, further indicating that NSCLC could be a key direction for future research on NKG2A-targeted drugs. AstraZeneca is currently rapidly advancing Phase III clinical trials, though relevant data has not yet been disclosed.

Different combinations of Monalizumab with anti-EGFR, anti-PD-L1, tyrosine kinase inhibitors, and chemotherapy drugs have been applied to various cancer indications, including resectable non-small cell lung cancer (NCT 03794544), PD-1 resistant non-small cell lung cancer patients (NCT 03833440), advanced head and neck squamous cell carcinoma patients (NCT 02643550), refractory chronic lymphocytic leukemia (NCT 02557516), other malignant hematological diseases after stem cell transplantation (NCT 02921685), and trials targeting advanced solid malignant tumors (NCT 02671435).

References

van Montfoort N, Borst L, Korrer MJ, et al. NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines. Cell. 2018;175(7):1744-1755.e15.
Borst L, van der Burg SH, van Hall T. The NKG2A-HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment. Clin Cancer Res. 2020;26(21):5549-5556.

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