Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 5, Pages 2094-2106Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI123955
Keywords
-
Categories
Funding
- National Medical Research Council of Singapore [NMRC/STaR/0025/2015a]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available