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Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic murine model

Cancer Gene Therapy volume 13, pages 753–761 (2006)Cite this article

Abstract

Previous studies have shown that the human melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) has tumor-suppressor activity in vitro and in vivo. Additionally, in vitro studies using human peripheral blood mononuclear cells indicate that mda-7/IL-24 has TH1 cytokine-like activity. However, the individual properties of mda-7/IL-24 have been previously examined separately. Thus, there is not a single study that has examined both, antitumor and proimmune properties of mda-7/IL-24. Furthermore, the tumor suppressive activity and the cytokine activity of mda-7/IL-24 have not been previously tested in an immunocompetent setting. We therefore in the present study evaluated the antitumor and immune properties of mda-7/IL-24 in a murine syngeneic tumor model. In vitro, adenovirus-mediated mda-7 gene (Ad-mda7) transfer to murine fibrosarcoma (UV2237m; MCA16) and normal (10T1/2) cells significantly inhibited growth (P=0.001) and induced apoptosis in tumor cells but not in normal cells. In vivo, intratumoral administration of Ad-mda7 resulted in significant inhibition of tumor growth (P<0.05), with a subset of mice showing complete tumor regression. We next evaluated the immune potentiation activity of Ad-mda7 in a cancer vaccine model. UV2237m cells transfected with Ad-mda7 and injected into syngeneic immunocompetent C3H mice were unable to grow; however, they did grow in immunocompromised nude mice. These tumor-free C3H mice, when challenged with parental tumor cells experienced no tumor growth, suggesting induction of systemic immunity. Moreover, splenocytes prepared from vaccinated C3H mice demonstrated higher proliferative activity and produced elevated levels of TH1 cytokines compared with those from control mice. An in vitro subset analysis of splenocytes from vaccinated mice demonstrated a significant increase in the CD3+CD8+ but not the CD3+CD4+ cell population (P=0.019). Thus Ad-mda7 treatment of syngeneic tumors induces tumor cell death and promotes immune activation, leading to anticancer immunity.

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Acknowledgements

We thank Karen Ramirez for help with the fluorescence-activated cell sorting analysis and Debbie Smith for editorial assistance. This work was supported by funds from the National Cancer Institute Grants RO1 CA102716 (Ramesh), PO1 CA06294 (Ramesh), CA89778 (Chada), CA88421 (Chada), CA097598 (Chada) and Cancer Center Support Grant CA16672; Texas Higher Education Coordinating Board ATP/ARP Grant 003657-0078-2001 (Ramesh); Institutional Research Grant (Ramesh); WM Keck Gene Therapy Grant (Ramesh) and sponsored research agreement with Introgen Therapeutics Inc.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R Miyahara, S Banerjee & R Ramesh

  2. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Kawano, C Efferson, N Tsuda & C G Ioannides

  3. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Miyahara

  4. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Chada

  5. Introgen Therapeutics Inc., Houston, TX, USA

    S Chada

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  1. R Miyahara
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Correspondence to R Ramesh.

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Miyahara, R., Banerjee, S., Kawano, K. et al. Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic murine model. Cancer Gene Ther 13, 753–761 (2006). https://doi.org/10.1038/sj.cgt.7700954

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