Rosuvastatin Enhances VSV-G Lentiviral Transduction of NK Cells via Upregulation of the Low-Density Lipoprotein Receptor

Ying Gong; Roel G J Klein Wolterink; Ian Janssen; Arjan J Groot; Gerard M J Bos; Wilfred T V Germeraad

doi:10.1016/j.omtm.2020.03.017

Rosuvastatin Enhances VSV-G Lentiviral Transduction of NK Cells via Upregulation of the Low-Density Lipoprotein Receptor

Mol Ther Methods Clin Dev. 2020 Mar 29:17:634-646. doi: 10.1016/j.omtm.2020.03.017. eCollection 2020 Jun 12.

Authors

Ying Gong^{1

2}, Roel G J Klein Wolterink^{1

2}, Ian Janssen^{1

2}, Arjan J Groot^{2

3}, Gerard M J Bos^{1

2

4}, Wilfred T V Germeraad^{1

2

4}

Affiliations

¹ Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center+, Maastricht, the Netherlands.
² GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
³ Department of Radiology, Maastricht University, Maastricht, the Netherlands.
⁴ CiMaas BV, Maastricht, the Netherlands.

Abstract

Adoptive natural killer (NK) cell therapy is attaining promising clinical outcomes in recent years, but improvements are needed. Genetic modification of NK cells with a tumor antigen-specific receptor on their surface coupled to intracellular signaling domains may lead to enhanced cytotoxicity against malignant cells. One of the most common approaches is by lentivirus-mediated transduction. However, NK cells are difficult to transduce and various methods have been attempted with different success rates. Because the low-density lipoprotein-receptor (LDLR) is the receptor of vesicular stomatitis virus (VSV) and is expressed only at low levels on NK cells, we tested the potential of 5 statins and 5 non-statin compounds to increase the LDLR expression, thereby facilitating viral transduction. We found that the transduction efficiency of VSV-G pseudotyped lentivirus is augmented by statins that induced higher LDLR expression. In both NK-92 cells and primary NK cells, the transduction efficiency increased after treatment with statins. Furthermore, statins have been reported to suppress NK cell cytotoxicity; however, we showed that this can be completely reversed by adding geranylgeranyl-pyrophosphate (GGPP). Among the statins tested, we found that the combination of rosuvastatin with GGPP most potently improved viral transduction without affecting the cytotoxic properties of the NK cells.

Keywords: GGPP; LDLR; VSV-G; lentiviral transduction; natural killer cells; rosuvastatin; statins.