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UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells.
Samudio I, Rezvani K, Shaim H, Hofs E, Ngom M, Bu L, Liu G, Lee JT, Imren S, Lam V, Poon GF, Ghaedi M, Takei F, Humphries K, Jia W, Krystal G. Blood 2016 [Epub ahead of print]
Herein we demonstrate that oncolytic herpes simplex virus -1 (HSV-1) potently activates human peripheral blood mononuclear cells (PBMC) to lyse leukemic cell lines and primary acute myeloid leukemia samples, but not healthy allogeneic lymphocytes. Intriguingly, we found that ultraviolet light (UV)-inactivated HSV-1 (UV-HSV-1) is equally effective in promoting PBMC cytolysis of leukemic cells, and is 1,000 to 10,000-fold more potent at stimulating innate anti-leukemic responses than UV-inactivated cytomegalovirus, vesicular stomatitis virus, reovirus or adenovirus. Mechanistically, UV-HSV-1 stimulates PBMC cytolysis of leukemic cells, partly via TLR-2/PKC/NFκB signaling, and potently stimulates expression of CD69, degranulation, migration, and cytokine production in NK cells, suggesting that surface components of UV-HSV-1 directly activate NK cells. Importantly, UV-HSV-1 synergizes with IL-15 and IL-2 in inducing activation and cytolytic activity of NK cells. Additionally, UV-HSV-1 stimulates glycolysis and fatty acid oxidation-dependent oxygen consumption in NK cells, but only glycolysis is required for their enhanced anti-leukemic activity. Lastly, we demonstrate that T cell-depleted human PBMC exposed to UV-HSV-1 provide a survival benefit in a murine xenograft model of human AML. Taken together, our results support the preclinical development of UV-HSV-1 as an adjuvant, alone or in combination with IL-15, for allogeneic donor mononuclear cell infusions to treat AML.