title: Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model.
abstract: Interleukin (IL)-12 is a potent antitumor cytokine. However, immunosuppressive tumor microenvironments containing transforming growth factor-β (TGF-β) attenuate cytokine-mediated antitumor immune responses. To enhance the efficacy of IL-12-mediated cancer immunotherapy, decorin (DCN) was explored as an adjuvant for overcoming TGF-β-mediated immunosuppression. We designed and generated a novel oncolytic adenovirus (Ad) coexpressing IL-12 and DCN (RdB/IL12/DCN). RdB/IL12/DCN-treated tumors showed significantly greater levels of interferon (IFN)-γ, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IFN-γ-secreting immune cells than tumors treated with cognate control oncolytic Ad expressing a single therapeutic gene (RdB/DCN or RdB/IL12). Moreover, RdB/IL12/DCN attenuated intratumoral TGF-β expression, which positively correlated with reduction of Treg cells in draining lymph nodes and tumor tissues. Furthermore, tumor tissue treated with RdB/IL12/DCN showed increases infiltration of CD8+ T cells and proficient viral spreading within tumor tissues. These results demonstrated that an oncolytic Ad co-expressing IL-12 and DCN induces a potent antitumor immune response via restoration of antitumor immune function in a weakly immunogenic murine 4T1 orthotopic breast cancer model. These findings provide new insights into the therapeutic mechanisms of IL-12 plus DCN, making it a promising cancer immunotherapeutic agent for overcoming tumor-induced immunosuppression.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Korea.
authors.forename: Eonju
authors.initials: E
authors.lastname: Oh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Korea.
authors.forename: JinWoo
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seongdong-gu, Seoul 133-791, Korea.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D058575:Decorin / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D016207:Cytokines; C546878:DCN protein, human; D058575:Decorin; D018664:Interleukin-12
keywords: IL-12; TGF-β; Treg; decorin; oncolytic adenovirus