Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12RΒ2 or IL-18Rα

I. K. Choi, J. S. Lee, S. N. Zhang, J. Park, K. M. Lee, C. H. Sonn, C. O. Yun

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)898-909
Number of pages12
JournalGene Therapy
Volume18
Issue number9
DOIs
Publication statusPublished - 2011 Sep

Keywords

  • IL-12
  • IL-18
  • T cells expressing IL-12Rβ2 or IL-18Rα
  • cancer immunogene therapy
  • oncolytic adenovirus

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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