title: Oncolytic adenovirus expressing IL-23 and p35 elicits IFN-γ- and TNF-α-co-producing T cell-mediated antitumor immunity.
abstract: Cytokine immunogene therapy is a promising strategy for cancer treatment. Interleukin (IL)-12 boosts potent antitumor immunity by inducing T helper 1 cell differentiation and stimulating cytotoxic T lymphocyte and natural killer cell cytotoxicity. IL-23 has been proposed to have similar but not overlapping functions with IL-12 in inducing Th1 cell differentiation and antitumor immunity. However, the therapeutic effects of intratumoral co-expression of IL-12 and IL-23 in a cancer model have yet to be investigated. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral inoculation of oncolytic adenovirus co-expressing IL-23 and p35, RdB/IL23/p35. Intratumoral administration of RdB/IL23/p35 elicited strong antitumor effects and increased survival in a murine B16-F10 syngeneic tumor model. The levels of IL-12, IL-23, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were elevated in RdB/IL23/p35-treated tumors. Moreover, the proportion of regulatory T cells was markedly decreased in mice treated with RdB/IL23/p35. Consistent with these data, mice injected with RdB/IL23/p35 showed massive infiltration of CD4(+) and CD8(+) T cells into the tumor as well as enhanced induction of tumor-specific immunity. Importantly, therapeutic mechanism of antitumor immunity mediated by RdB/IL23/p35 is associated with the generation and recruitment of IFN-γ- and TNF-α-co-producing T cells in tumor microenvironment. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-23 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Eonju
authors.initials: E
authors.lastname: Oh
authors.forename: Jaesung
authors.initials: J
authors.lastname: Kim
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D018628:Gene Dosage; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma