Abstract
ZD55-IL-24 is similar but superior to the oncolytic adenovirus ONYX-015, yet the exact mechanism underlying the observed therapeutic effect is still not well understood. Here we sought to elucidate the underlying antitumor mechanism of ZD55-IL-24 in both immunocompetent and immunocompromised mouse model. We find that ZD55-IL-24 eradicates established melanoma in B16-bearing immunocompetent mouse model not through the classic direct killing pathway, but mainly through the indirect pathway of inducing systemic antitumor immunity. Inconsistent with the current prevailing view, our further results suggest that ZD55-IL-24 can induce antitumor immunity in B16-bearing immunocompetent mouse model in fact not due to its ability to lyse tumor cells and release the essential elements, such as tumor-associated antigens (TAAs), but due to its ability to put a “nonself” label in tumor cells and then turn the tumor cells from the “self” state into the “nonself” state without tumor cell death. The observed anti-melanoma efficacy of ZD55-IL-24 in B16-bearing immunocompetent mouse model was practically caused only by the viral vector. In addition, we also notice that ZD55-IL-24 can inhibit tumor growth in B16-bearing immunocompetent mouse model through inhibiting angiogenesis, despite it plays only a minor role. In contrast to B16-bearing immunocompetent mouse model, ZD55-IL-24 eliminates established melanoma in A375-bearing immunocompromised mouse model mainly through the classic direct killing pathway, but not through the antitumor immunity pathway and anti-angiogenesis pathway. These findings let us know ZD55-IL-24 more comprehensive and profound, and provide a sounder theoretical foundation for its future modification and drug development.
Highlights
Oncolytic viruses are therapeutically useful viruses that selectively infect and damage cancerous tissues without causing harm to normal tissues[1]
Our further results showed that ZD55-IL-24 could effectively kill human tumor cells in vitro, though it was not observed in matched murine tumor cells (Supplementary Fig. 1A–H), excluding the possibility of the ZD55-IL-24 we used were inactive
We found that the peripheral blood mononuclear cells (PBMCs) obtained from ZD55-IL-24-treated mice could kill ZD55-IL-24-treated B16 cells in vitro (Fig. 6M), indicating that the anti-viral specific immune response induced by ZD55-IL-24 could act against the tumor cells infected with ZD55-IL-24, indirectly demonstrating that ZD55-IL-24 viral infection could result in the presentation of “nonself” viral epitopes on the surface of tumor cells
Summary
Oncolytic viruses are therapeutically useful viruses that selectively infect and damage cancerous tissues without causing harm to normal tissues[1]. ZD55-IL-24, one of the most effective armed oncolytic viruses developed so far, was constructed by cloning the foreign antitumor gene mda-7/interleukin-24 (IL-24) into the tumor-targeting replicative viral vector ZD552,3. Hu et al Cell Death and Disease (2020)11:1022 foreign genes[4] Another two differences between ZD55 and other oncolytic adenoviruses are that ZD55 is an adenovirus type 5 homozygote and has an intact E3 region, whereas the most of other oncolytic adenoviruses are adenovirus chimaeras (e.g., ONYX-015 is a type 2/5 chimaera and Colo-Ad1 is a type 11/3 chimaera)[1,4,5] or have major deletions within the E3 region (e.g., ONYX015, H101, and CG0070)[1,5,6]. Oncolytic viruses are difficult to be used to treat the vast majority of tumors in clinic To overcome this limitation, we constructed a PEG/Lipids/calcium phosphate (CaP)-OncoAd (PLC-OncoAd) delivery system for ZD55-IL-24 in our recent work[12]. We focused on its application in our past research and knew little about its antitumor mechanism[2,7,8,9,12,13]
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