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An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts
Che-Yuan Hu1, Chi-Feng Hung2, Pi-Che Chen2
1Department of Urology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Abstract:
Immunotherapy has emerged as a promising modality for cancer treatment. Dendritic cell immunoreceptor (DCIR), a C-type lectin receptor, is expressed mainly by dendritic cells (DCs) and mediates inhibitory intracellular signaling. Inhibition of DCIR activation may enhance antitumor activity. DCIR is encoded by CLEC4A in humans and by Clec4a2 in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting Clec4a2 into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8+ T cell immune responses. Various oncolytic adenoviruses have been developed in clinical trials. Previously, we have developed Ad.LCY, an oncolytic adenovirus regulated by Oct4 and hypoxia, and demonstrated its antitumor efficacy. Here, we generated a Clec4a2 shRNA-expressing oncolytic adenovirus derived from Ad.LCY, designated Ad.shDCIR, aimed at inducing more robust antitumor immune responses. Our results show that treatment with Ad.shDCIR reduced Clec4a expression in DCs in cell culture. Furthermore, Ad.shDCIR exerted cytolytic effects solely on MBT-2 bladder cancer cells but not on normal NIH 3T3 mouse fibroblasts, confirming the tumor selectivity of Ad.shDCIR. Compared to Ad.LCY, Ad.shDCIR induced higher cytotoxic T lymphocyte (CTL) activity in MBT-2 tumor-bearing immunocompetent mice. In addition, Ad.shDCIR and Ad.LCY exhibited similar antitumor effects on inhibiting tumor growth. Notably, Ad.shDCIR was superior to Ad.LCY in prolonging the survival of tumor-bearing mice. In conclusion, Ad.shDCIR may be further explored as a combination therapy of virotherapy and immunotherapy for bladder cancer and likely other types of cancer.
Insights
A novel oncolytic adenovirus, Ad.shDCIR, targets dendritic cell immunoreceptor (DCIR) to enhance antitumor immunity. This therapy shows promise for bladder cancer by boosting T cell responses and improving survival.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Immunotherapy offers a promising approach for cancer treatment.
- Dendritic cell immunoreceptor (DCIR) signaling inhibits antitumor activity.
- Targeting DCIR can potentially enhance anti-cancer immune responses.
Purpose of the Study:
- To develop and evaluate an oncolytic adenovirus expressing short hairpin RNA (shRNA) against DCIR (Ad.shDCIR).
- To assess the efficacy of Ad.shDCIR in enhancing antitumor immunity and its therapeutic potential for bladder cancer.
Main Methods:
- Generation of Ad.shDCIR, an oncolytic adenovirus derived from Ad.LCY, encoding Clec4a2 shRNA.
- In vitro assessment of Ad.shDCIR's cytolytic activity against bladder cancer cells and normal fibroblasts.
- In vivo evaluation of Ad.shDCIR's impact on DCIR expression, cytotoxic T lymphocyte (CTL) activity, tumor growth inhibition, and survival in tumor-bearing mice.
Main Results:
- Ad.shDCIR effectively reduced DCIR expression in dendritic cells (DCs).
- Ad.shDCIR demonstrated tumor-selective cytolysis of MBT-2 bladder cancer cells.
- Ad.shDCIR significantly increased CTL activity and prolonged survival in tumor-bearing mice compared to the control adenovirus Ad.LCY.
Conclusions:
- Ad.shDCIR represents a promising strategy combining oncolytic virotherapy and immunotherapy.
- This novel agent warrants further investigation for bladder cancer treatment and potentially other malignancies.
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