Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a deadly neoplasm. Oncolytic viruses have tumorolytic and immune response-boosting effects and present great potential for PDAC management. We used LIGHT-armed myxoma virus (vMyx-LIGHT) loaded ex vivo into human adipose-derived mesenchymal stem cells (ADSCs...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/8/2022 |
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| author | Joanna Jazowiecka-Rakus Aleksander Sochanik Agata Hadryś Wojciech Fidyk Ewa Chmielik Masmudur M. Rahman Grant McFadden |
| author_facet | Joanna Jazowiecka-Rakus Aleksander Sochanik Agata Hadryś Wojciech Fidyk Ewa Chmielik Masmudur M. Rahman Grant McFadden |
| author_sort | Joanna Jazowiecka-Rakus |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) is a deadly neoplasm. Oncolytic viruses have tumorolytic and immune response-boosting effects and present great potential for PDAC management. We used LIGHT-armed myxoma virus (vMyx-LIGHT) loaded ex vivo into human adipose-derived mesenchymal stem cells (ADSCs) to evaluate murine PDAC treatment in conjunction with gemcitabine (GEM). The cytotoxicity of this treatment was confirmed in vitro using human and murine pancreatic cancer cell cultures, which were more sensitive to the combined approach and largely destroyed. Unlike cancer cells, ADSCs sustain significant viability after infection. The in vivo administration of vMyx-LIGHT-loaded ADSCs and gemcitabine was evaluated using immunocompetent mice with induced orthotopic PDAC lesions. The expression of virus-encoded LIGHT increased the influx of T cells to the tumor site. Shielded virus followed by gemcitabine improved tumor regression and survival. The addition of gemcitabine slightly compromised the adaptive immune response boost obtained with the shielded virus alone, conferring no survival benefit. ADSCs pre-loaded with vMyx-LIGHT allowed the effective transport of the oncolytic construct to PDAC lesions and yielded significant immune response; additional GEM administration failed to improve survival. In view of our results, the delivery of targeted/shielded virus in combination with TGF-β ablation and/or checkpoint inhibitors is a promising option to improve the therapeutic effects of vMyx-LIGHT/ADSCs against PDAC in vivo. |
| first_indexed | 2024-03-09T11:02:49Z |
| format | Article |
| id | doaj.art-5688f5b4ec6f40a58e1a2690f57f2336 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T11:02:49Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5688f5b4ec6f40a58e1a2690f57f23362023-12-01T01:08:55ZengMDPI AGCancers2072-66942022-04-01148202210.3390/cancers14082022Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic AdenocarcinomaJoanna Jazowiecka-Rakus0Aleksander Sochanik1Agata Hadryś2Wojciech Fidyk3Ewa Chmielik4Masmudur M. Rahman5Grant McFadden6Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże AK 15, 44-102 Gliwice, PolandCenter for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże AK 15, 44-102 Gliwice, PolandCenter for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże AK 15, 44-102 Gliwice, PolandDepartment of Bone Marrow Transplantation and Hematology-Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże AK 15, 44-102 Gliwice, PolandTumor Pathology Department, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże AK 15, 44-102 Gliwice, PolandBiodesign Institute, Arizona State University, Tempe, AZ 85287, USABiodesign Institute, Arizona State University, Tempe, AZ 85287, USAPancreatic ductal adenocarcinoma (PDAC) is a deadly neoplasm. Oncolytic viruses have tumorolytic and immune response-boosting effects and present great potential for PDAC management. We used LIGHT-armed myxoma virus (vMyx-LIGHT) loaded ex vivo into human adipose-derived mesenchymal stem cells (ADSCs) to evaluate murine PDAC treatment in conjunction with gemcitabine (GEM). The cytotoxicity of this treatment was confirmed in vitro using human and murine pancreatic cancer cell cultures, which were more sensitive to the combined approach and largely destroyed. Unlike cancer cells, ADSCs sustain significant viability after infection. The in vivo administration of vMyx-LIGHT-loaded ADSCs and gemcitabine was evaluated using immunocompetent mice with induced orthotopic PDAC lesions. The expression of virus-encoded LIGHT increased the influx of T cells to the tumor site. Shielded virus followed by gemcitabine improved tumor regression and survival. The addition of gemcitabine slightly compromised the adaptive immune response boost obtained with the shielded virus alone, conferring no survival benefit. ADSCs pre-loaded with vMyx-LIGHT allowed the effective transport of the oncolytic construct to PDAC lesions and yielded significant immune response; additional GEM administration failed to improve survival. In view of our results, the delivery of targeted/shielded virus in combination with TGF-β ablation and/or checkpoint inhibitors is a promising option to improve the therapeutic effects of vMyx-LIGHT/ADSCs against PDAC in vivo.https://www.mdpi.com/2072-6694/14/8/2022adipose tissue-derived stem cells (ADSCs)oncolytic virusmyxoma virusoncolytic virotherapypancreatic ductal adenocarcinomaimmune response |
| spellingShingle | Joanna Jazowiecka-Rakus Aleksander Sochanik Agata Hadryś Wojciech Fidyk Ewa Chmielik Masmudur M. Rahman Grant McFadden Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma Cancers adipose tissue-derived stem cells (ADSCs) oncolytic virus myxoma virus oncolytic virotherapy pancreatic ductal adenocarcinoma immune response |
| title | Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma |
| title_full | Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma |
| title_fullStr | Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma |
| title_full_unstemmed | Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma |
| title_short | Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma |
| title_sort | combination of light tnfsf14 armed myxoma virus pre loaded into adscs and gemcitabine in the treatment of experimental orthotopic murine pancreatic adenocarcinoma |
| topic | adipose tissue-derived stem cells (ADSCs) oncolytic virus myxoma virus oncolytic virotherapy pancreatic ductal adenocarcinoma immune response |
| url | https://www.mdpi.com/2072-6694/14/8/2022 |
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