Abstract
Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses—the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)—to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.
Highlights
Oncolytic viruses (OVs) infect malignant cells and replicate selectively within them
Two oncolytic adenoviruses were evaluated in this work: the E1A CR2-deleted Ad5 mutant dl[922-947], which we have previously shown has significant efficacy in ovarian cancer models,[9,10] and the chimeric Ad3/ Ad11p mutant enadenotucirev, which was generated by directed evolution[11] and is currently being tested in early phase clinical trials in ovarian (ClinicalTrials.gov: NCT02053220)[12] and other cancers (ClinicalTrials.gov: NCT02028117)
There was no detectable fluorescence in the established Natural killer (NK) cell line NK-92 following Ad CMV green fluorescent protein (GFP) infection (Figure S1A), in contrast to a panel of ovarian cancer (OC) cells (p = 0.0002)
Summary
Oncolytic viruses (OVs) infect malignant cells and replicate selectively within them. This selective replication induces direct cytotoxicity and triggers profound innate and adaptive immune responses,[1,2,3] which have the potential both to potentiate and reduce the anti-cancer activity of the OVs.[4]. Previous studies suggested that NK cells are activated by oncolytic reovirus treatment in patients[15] and are necessary for successful maraba virus therapy in murine models.[16] By contrast, NK cells may limit the efficacy of an oncolytic herpes simplex virus 1 (HSV-1) in murine glioblastoma models,[17] which may be reversed by transforming growth factor-b (TGF-b)[18] and the proteasome inhibitor bortezomib.[19] the role of NK cells in oncolytic adenovirus therapy has not been thoroughly explored, expression of Ad5 E1A protein can sensitize tumor cells to NK-mediated lysis,[20] and several studies have implicated NK cells in the elimination of non-replicating E1-deleted adenovirus vectors.[21,22]
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