Author of

• 14490

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  P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 14555

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    P2.04-065 - Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies (ID 3006)

    09:30 - 09:30  |  Author(s): M. Watanabe
    • Abstract

    Background:
    We previously identified the tumor suppressor gene REIC/Dkk-3 whose expression is reduced in many human cancers, and overexpression of REIC/Dkk-3 by an adenovirus (Ad-REIC) exhibited a dramatic therapeutic effect on several human cancers through a mechanism triggered by endoplasmic reticulum (ER) stress. In addition to the direct anti-tumor effect, we also have shown that Ad-REIC has a host-mediated bystander effect on human prostate cancer and scirrhous gastric cancer through REIC-mediated cancer vaccination and production of IL-7. In this study, we examined possible direct and indirect distant bystander effects of Ad-REIC via activation of systemic anti-tumor immunity on thoracic malignancies.
    
    Methods:
    We examined anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma (MM) cell lines in vitro. In addition, we examined the direct and distant bystander effect of Ad-REIC in bilateral flank allograft tumor model using immunocompetent BALB/c mice. Mice received intratumoral injection of Ad-REIC into the right-flank tumors, and the effect in bilateral-flank tumors were examined. Dissected bilateral flank tumors after sacrifice were also subjected to immunohistochemical analysis.
    
    Results:
    Ad-REIC treatment showed anti-tumor effect in many of lung cancer and MM cell lines in vitro due to the activation of c-Jun N-terminal kinase (JNK). REIC/Dkk-3 was highly expressed after Ad-SGE-REIC treatment in Ad-SGE-REIC sensitive cell lines, while it was not or weakly expressed in some cells, which were resist to Ad-SGE-REIC treatment. In an in vivo model, Ad-REIC treatment inhibited the tumorigenic growth of not only direct injected tumor but also distant non-injected tumor. In immunohistochemical examination, infiltration of CD49b positive NK cells and expression of MHC Class-I molecules H60 and Rae-1 were revealed in bilateral tumors, suggesting that Ad-REIC treatment showed bystander anti-tumor effect through immune system-mediated apoptosis, and protein expression of MHC class-I molecules induces NK cell infiltration to the tumor.
    
    Conclusion:
    We newly revealed that Ad-REIC treatment induced MHC Class-I expression both in primary and distant tumor sites, which lead NK cell infiltration. Ad-REIC treatment showed not only direct anti-tumor effect but also indirect bystander effect through immune system stimulation in immunocompetent mice model.　Our findings suggest that Ad-REIC therapy is a promising treatment for MM and lung cancer