Oncolytic adenovirus serotype 35 mediated tumor growth suppression via efficient activation of antitumor immunity.

Abstract

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 immune cells in the tumor growth-suppression effects of OAd35 was evaluated in asialo GM1 (aGM1)⁺ 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 1 (IFNAR1) knockout and toll-like receptor 9 knockout mice.

Results: OAd35 efficiently induced tumor infiltration of activated natural killer (NK) cells and T cells after intratumoral administration in B16 tumor-bearing mice. Depletion of aGM1⁺ cells, including NK cells and a portion of CD8⁺ T cells, significantly hindered the OAd35-mediated tumor growth suppression in C57BL/6J wild-type mice and BALB/c nude mice. In IFNAR1 knockout mice, OAd35-induced tumor infiltration of activated NK cells and OAd35-mediated tumor growth suppression were significantly attenuated.

Conclusions: These data described above suggested that immune cells, including aGM1⁺ cells, contributed to the antitumor effects of OAd35. OAd35 significantly promoted activation and tumor infiltration of NK cells. The type-I IFN signal was crucial for the OAd35-mediated tumor infiltration, activation of NK cells, and tumor growth suppression. These findings suggest that OAd35 is a promising cancer immunotherapy agent via its enhancement of the antitumor activities of immune cells.