title: Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα.
abstract: The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.
authors: Graduate Program for Nanomedical Science, Yonsei University, Seoul, South Korea.
authors: I-K
authors: IK
authors: Choi
authors: J-S
authors: JS
authors: Lee
authors: S-N
authors: SN
authors: Zhang
authors: J
authors: J
authors: Park
authors: C H
authors: CH
authors: Sonn
authors: K-M
authors: KM
authors: Lee
authors: C-O
authors: CO
authors: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D053707:Receptors, Interleukin-12 / Q000378:metabolism*; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C508439:IL12RB2 protein, human; D020382:Interleukin-18; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D018664:Interleukin-12