Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells

2019/03/12 by Takahiro Kamiya, See Voon Seow, Desmond Wong +3 · 343 citations
Chemistry · Immunology and Microbiology · Medicine · Neuroscience · #Biology #Blocking (statistics) #CAR-T cell therapy research #Cancer research #Cell biology #Chemistry #Computer network #Computer science #Genetics #Immune Cell Function and Interaction #Inhibitory postsynaptic potential #Neuroscience #Receptor #T-cell and B-cell Immunology

paper · pdf · doi:10.1172/jci123955

published in Journal of Clinical Investigation 129(5), 2094-2106 (American Society for Clinical Investigation)

openalex publication_date 2019/03/12 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28

Abstract

A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA-E in tumor cells, which suppresses natural killer (NK) cell activity via ligation of the NK inhibitory receptor CD94/NKG2A. Gene expression data from approximately 10,000 tumor samples showed widespread HLAE expression, with levels correlating with those of KLRC1 (NKG2A) and KLRD1 (CD94). To bypass HLA-E inhibition, we developed a way to generate highly functional NK cells lacking NKG2A. Constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody were linked to endoplasmic reticulum-retention domains. After retroviral transduction in human peripheral blood NK cells, these NKG2A Protein Expression Blockers (PEBLs) abrogated NKG2A expression. The resulting NKG2Anull NK cells had higher cytotoxicity against HLA-E-expressing tumor cells. Transduction of anti-NKG2A PEBL produced more potent cytotoxicity than interference with an anti-NKG2A antibody and prevented de novo NKG2A expression, without affecting NK cell proliferation. In immunodeficient mice, NKG2Anull NK cells were significantly more powerful than NKG2A+ NK cells against HLA-E-expressing tumors. Thus, NKG2A downregulation evades the HLA-E cancer immune-checkpoint, and increases the anti-tumor activity of NK cell infusions. Because this strategy is easily adaptable to current protocols for clinical-grade immune cell processing, its clinical testing is feasible and warranted.

Citations

• TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells

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