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

被引:268
作者
Kamiya, Takahiro [1 ,2 ]
Seow, See Voon [1 ,2 ]
Wong, Desmond [1 ,2 ]
Robinson, Murray [3 ]
Campana, Dario [1 ,2 ]
机构
[1] Natl Univ Singapore, Dept Pediat, Singapore, Singapore
[2] Natl Univ Singapore, Natl Univ Canc Inst Singapore, Singapore, Singapore
[3] MediSix Therapeut, Singapore, Singapore
基金
英国医学研究理事会;
关键词
NATURAL-KILLER-CELLS; HLA-E; T-CELLS; IFN-GAMMA; RECOGNITION; CD94/NKG2A; CD94; IMMUNOTHERAPY; CYTOTOXICITY; LYMPHOCYTES;
D O I
10.1172/JCI123955
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA class I molecule (HLA-E) in tumor cells, which suppresses NK cell activity via ligation of the NK inhibitory receptor CD94/NK group 2 member A (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 NKG2A(null) 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, NKG2A(null) NK cells were substantially more powerful than NKG2A(+) NK cells against HLA-E-expressing tumors. Thus, NKG2A downregulation evades the HLA-E cancer immune checkpoint and increases the antitumor 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.
引用
收藏
页码:2094 / 2106
页数:13
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