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Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells
Takahiro Kamiya, … , Murray Robinson, Dario Campana
Takahiro Kamiya, … , Murray Robinson, Dario Campana
Published March 12, 2019
Citation Information: J Clin Invest. 2019;129(5):2094-2106. https://doi.org/10.1172/JCI123955.
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Research Article Immunology Oncology

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

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Abstract

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 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 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

Takahiro Kamiya, See Voon Seow, Desmond Wong, Murray Robinson, Dario Campana

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Figure 1

Expression of HLAE in tumors and its relation with KLRC1 (NKG2A) expression.

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Expression of HLAE in tumors and its relation with KLRC1 (NKG2A) express...
(A) Expression of HLAE in 10,375 specimens from 33 tumor types; box plots with data from every sample superimposed show log10 HLAE gene transcripts per kilobase million (TPM) in adrenocortical carcinoma (ACC), BLCA, BRCA, CESC, cholangiocarcinoma (CHOL), COAD, diffuse large B cell lymphoma (DLBC), esophageal carcinoma (ESCA), GBM, HNSC, kidney chromophobe (KICH), KIRC, kidney renal papillary cell carcinoma (KIRP), AML, LGG, liver hepatocellular carcinoma (LIHC), LUAD, LUSC, mesothelioma (MESO), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), PCPG, PRAD, READ, SARC, SKCM, STAD, testicular germ cell tumors (TGCT), THCA, THYM, uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS), uveal melanoma (UVM). Box boundaries, first and third quartile range; whisker, interquartile range (first quartile to third quartile range) ×1.5. (B) Shown is log2 normalized expression of HLAE with KLRC1, KLRD1 (CD94), or KLRC2 (NKG2C) in 9520 tumors analyzed (tumors lacking KLRC1 expression were excluded). Pearson’s correlation coefficient and linear regression line are shown. (C) Relation between log2 normalized expression of HLAE and KLRC1. The 9520 tumor specimens were ordered by expression of HLAE or KLRC1; the corresponding expression of KLRC1 and HLAE is shown. (D) Relation between HLAE and KLRC1 expression in tumors with high Pearson’s correlation coefficient.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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