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UV Light–inactivated HSV-1 Stimulates Natural Killer Cell–induced Killing of Prostate Cancer Cells

Samudio, Ismael*,†; Hofs, Elyse; Cho, Brandon; Li, Michael; Bolduc, Kayla; Bu, Luke; Liu, Guoyu; Lam, Vivian; Rennie, Paul§; Jia, William; Elisia, Ingrid; Krystal, Gerald

doi: 10.1097/CJI.0000000000000261
Basic Studies
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Herein we demonstrate that ultraviolet light–inactivated Herpes Simplex Virus-1 (UV-HSV-1) stimulates peripheral blood mononuclear cells (PBMCs) to lyse both androgen-sensitive and androgen-independent prostate cancer (PrCA) cell lines, but not the benign prostatic hyperplastic epithelial cell line, BPH-1, and is 1000–10,000-fold more potent at stimulating this killing than ultraviolet light-inactivated Vesicular Stomatitis Virus, adenovirus, reovirus or cytomegalovirus. Among PBMCs, natural killer (NK) cells appear to be a major cell type involved in this killing and UV-HSV-1 appears to directly and potently stimulate NK cell expression of CD69, degranulation, cytokine production, and migration to IL-8 in PC3 conditioned medium. We also found that UV-HSV-1 stimulates glycolysis in PBMCs and NK cells, and that 2-deoxyglucose and the protein kinase C inhibitor, Go6976, and the NFκB inhibitor, Bay 11-7082, all abrogate UV-HSV-1 activated killing of PC3 cells by PBMCs and NK cells. Using neutralizing anti-Toll-like receptor 2 (TLR2) we found that UV-HSV-1, like HSV-1, activates NK cells via TLR2. Taken together, these results are consistent with Toll-like receptor 2 ligands on UV-HSV-1 stimulating TLR2 on NK cells to activate protein kinase C, leading to enhanced glycolysis and NFκB activation, both of which play a critical role in this anti-PrCA innate immune response. Importantly, UV-HSV-1 synergizes with IL-15 to increase the cytolytic activity of PBMCs against PC3 cells and there was considerable donor-to-donor variation in killing ability. These results support the preclinical development of UV-HSV-1 as an adjuvant, in combination with IL-15, for cell infusions of healthy, preselected NK cells to treat PrCA.

*Research and Innovation Program in Acute and Chronic Leukemia, Bogota, Colombia

Terry Fox Laboratory, British Columbia Cancer

Brain Research Centre, University of British Columbia

§Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada

I.S.: designed and conducted experiments, analyzed data, and wrote a draft of the paper. E.H., B.C., M.L., K.B., V.L.: conducted experiments and analyzed data. L.B. and G.L.: generated and titered the HSV-1 viral preparation used for these studies. P.R., W.J., I.E., and G.K.: designed experiments, analyzed data, and wrote the paper.

Reprints: Gerald Krystal, Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada, V5Z 1L3 (e-mail: gkrystal@bccrc.ca).

Received October 30, 2018

Accepted February 6, 2019

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