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Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic
R Miyahara1, S Banerjee, K Kawano
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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.
Insights
The melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) gene therapy shows significant tumor suppression and induces a potent immune response in preclinical cancer models. This dual action promotes systemic anticancer immunity.
Area of Science:
- Oncology
- Immunology
- Gene Therapy
Background:
- Melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) exhibits known tumor-suppressor and TH1 cytokine-like activities.
- Previous research has examined these properties separately, often in non-immunocompetent models.
- A comprehensive evaluation in an immunocompetent setting was lacking.
Purpose of the Study:
- To investigate the combined antitumor and pro-immune effects of mda-7/IL-24.
- To assess these properties within a murine syngeneic tumor model, an immunocompetent system.
- To determine the potential of mda-7/IL-24 as a therapeutic agent for cancer.
Main Methods:
- Adenovirus-mediated mda-7 gene (Ad-mda7) transfer was used for in vitro and in vivo studies.
- Murine fibrosarcoma cells (UV2237m) and normal cells (10T1/2) were utilized.
- Intratumoral Ad-mda7 administration and a cancer vaccine model in syngeneic immunocompetent C3H mice were employed.
Main Results:
- Ad-mda7 significantly inhibited tumor cell growth and induced apoptosis in vitro, without affecting normal cells.
- Intratumoral Ad-mda7 administration led to significant tumor growth inhibition and complete regression in a subset of mice.
- Vaccination with Ad-mda7-transfected tumor cells induced systemic immunity, preventing tumor growth upon re-challenge and enhancing TH1 cytokine production and CD8+ T cell response.
Conclusions:
- Ad-mda7 demonstrates potent antitumor activity through direct tumor cell death.
- The gene therapy effectively promotes immune activation, leading to the development of systemic anticancer immunity.
- Ad-mda7 holds promise as a dual-action therapeutic strategy for cancer treatment.
