Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer
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...
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MDPI AG
2023-09-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2598 |
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| author | Che-Yuan Hu Chi-Feng Hung Pi-Che Chen Jia-Yu Hsu Chung-Teng Wang Ming-Derg Lai Yuh-Shyan Tsai Ai-Li Shiau Gia-Shing Shieh Chao-Liang Wu |
| author_facet | Che-Yuan Hu Chi-Feng Hung Pi-Che Chen Jia-Yu Hsu Chung-Teng Wang Ming-Derg Lai Yuh-Shyan Tsai Ai-Li Shiau Gia-Shing Shieh Chao-Liang Wu |
| author_sort | Che-Yuan Hu |
| collection | DOAJ |
| description | 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 <i>CLEC4A</i> in humans and by <i>Clec4a2</i> in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting <i>Clec4a2</i> into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8<sup>+</sup> 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 <i>Clec4a2</i> 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. |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T21:25:16Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-3d33ad029c674c0685ee1e0eeb188d692023-11-19T15:44:18ZengMDPI AGBiomedicines2227-90592023-09-011110259810.3390/biomedicines11102598Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder CancerChe-Yuan Hu0Chi-Feng Hung1Pi-Che Chen2Jia-Yu Hsu3Chung-Teng Wang4Ming-Derg Lai5Yuh-Shyan Tsai6Ai-Li Shiau7Gia-Shing Shieh8Chao-Liang Wu9Department of Urology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Urology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Urology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanImmunotherapy 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 <i>CLEC4A</i> in humans and by <i>Clec4a2</i> in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting <i>Clec4a2</i> into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8<sup>+</sup> 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 <i>Clec4a2</i> 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.https://www.mdpi.com/2227-9059/11/10/2598oncolytic adenovirusdendritic cell immunoreceptorimmunotherapydendritic cellOct4hypoxia |
| spellingShingle | Che-Yuan Hu Chi-Feng Hung Pi-Che Chen Jia-Yu Hsu Chung-Teng Wang Ming-Derg Lai Yuh-Shyan Tsai Ai-Li Shiau Gia-Shing Shieh Chao-Liang Wu Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer Biomedicines oncolytic adenovirus dendritic cell immunoreceptor immunotherapy dendritic cell Oct4 hypoxia |
| title | Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer |
| title_full | Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer |
| title_fullStr | Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer |
| title_full_unstemmed | Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer |
| title_short | Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer |
| title_sort | oct4 and hypoxia dual regulated oncolytic adenovirus armed with shrna targeting dendritic cell immunoreceptor exerts potent antitumor activity against bladder cancer |
| topic | oncolytic adenovirus dendritic cell immunoreceptor immunotherapy dendritic cell Oct4 hypoxia |
| url | https://www.mdpi.com/2227-9059/11/10/2598 |
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