Oncolytic adenovirus serotype 35 mediated tumor growth suppression via efficient activation and tumor infiltration of natural killer cells

Background Oncolytic adenoviruses (OAds) mediate superior antitumor effects both by inducing direct oncolysis and activating antitumor immunity. Previously, we developed a novel OAd fully composed of human adenovirus serotype 35 (OAd35). OAd35 efficiently killed a variety of human tumor cells; however, OAd35-mediated activation of antitumor immunity remains to be evaluated. In this study, we examined whether OAd35-induced activation of immune cells contributes to the antitumor effects of OAd35. Methods Tumor infiltration and activation of immune cells following intratumoral administration of OAd35 in tumor-bearing immune-competent and nude mice were analyzed. The involvement of natural killer (NK) cells in the tumor growth-suppression effects of OAd35 was evaluated in NK cell-depleted mice. The key signals for the OAd35-mediated tumor infiltration of NK cells were examined in interferon (IFN) alpha and beta receptor subunit 2 (IFNAR2) knockout and toll-like receptor 9 (TLR9) knockout mice. Results OAd35 efficiently induced tumor infiltration of activated NK cells. NK cell depletion apparently hindered the OAd35-mediated tumor growth suppression. In IFNAR2 knockout mice, OAd35-induced tumor infiltration of activated NK cells was significantly attenuated. OAd35 did not induce tumor infiltration of NK cells in TLR9 knockout mice, although OAd35 significantly activated NK cells and showed tumor growth suppression in TLR9 knockout mice. Conclusions OAd35 significantly promoted activation and tumor infiltration of NK cells, leading to OAd35-mediated efficient tumor growth suppression. The type-I IFN signal was crucial for the OAd35-mediated tumor infiltration and activation of NK cells. The TLR9 signal was highly related to tumor infiltration of NK cells, but not NK cell activation and antitumor effects of OAd35. OAd35 is expected to become a promising cancer immunotherapy agent via its enhancement of the antitumor activities of NK cells.