Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate
IntroductionLiver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin,...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1245708/full |
| _version_ | 1797681754348191744 |
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| author | Ken Liu Ken Liu Ken Liu Jinbiao Chen Yang Zhao Jade Boland Ka Ka Ting Glen Lockwood Catriona McKenzie James Kench Mathew A. Vadas Mathew A. Vadas Jennifer R. Gamble Jennifer R. Gamble Geoffrey W. McCaughan Geoffrey W. McCaughan Geoffrey W. McCaughan |
| author_facet | Ken Liu Ken Liu Ken Liu Jinbiao Chen Yang Zhao Jade Boland Ka Ka Ting Glen Lockwood Catriona McKenzie James Kench Mathew A. Vadas Mathew A. Vadas Jennifer R. Gamble Jennifer R. Gamble Geoffrey W. McCaughan Geoffrey W. McCaughan Geoffrey W. McCaughan |
| author_sort | Ken Liu |
| collection | DOAJ |
| description | IntroductionLiver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model.MethodsWe first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy.ResultsHuman data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups.DiscussionCD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one. |
| first_indexed | 2024-03-11T23:49:36Z |
| format | Article |
| id | doaj.art-dc2ca80bddc44224b7b4496b62a00d02 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T23:49:36Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-dc2ca80bddc44224b7b4496b62a00d022023-09-19T07:56:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12457081245708Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrateKen Liu0Ken Liu1Ken Liu2Jinbiao Chen3Yang Zhao4Jade Boland5Ka Ka Ting6Glen Lockwood7Catriona McKenzie8James Kench9Mathew A. Vadas10Mathew A. Vadas11Jennifer R. Gamble12Jennifer R. Gamble13Geoffrey W. McCaughan14Geoffrey W. McCaughan15Geoffrey W. McCaughan16AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaBiogerontology Group, ANZAC Research Institute, Sydney, NSW, AustraliaNew South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaNew South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaAW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCentenary Institute, University of Sydney, Sydney, NSW, AustraliaIntroductionLiver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model.MethodsWe first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy.ResultsHuman data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups.DiscussionCD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1245708/fullhepatocellular carcinomaangiogenesisvascular normalizationimmunotherapyhypoxia |
| spellingShingle | Ken Liu Ken Liu Ken Liu Jinbiao Chen Yang Zhao Jade Boland Ka Ka Ting Glen Lockwood Catriona McKenzie James Kench Mathew A. Vadas Mathew A. Vadas Jennifer R. Gamble Jennifer R. Gamble Geoffrey W. McCaughan Geoffrey W. McCaughan Geoffrey W. McCaughan Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate Frontiers in Immunology hepatocellular carcinoma angiogenesis vascular normalization immunotherapy hypoxia |
| title | Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate |
| title_full | Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate |
| title_fullStr | Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate |
| title_full_unstemmed | Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate |
| title_short | Novel miRNA-based drug CD5-2 reduces liver tumor growth in diethylnitrosamine-treated mice by normalizing tumor vasculature and altering immune infiltrate |
| title_sort | novel mirna based drug cd5 2 reduces liver tumor growth in diethylnitrosamine treated mice by normalizing tumor vasculature and altering immune infiltrate |
| topic | hepatocellular carcinoma angiogenesis vascular normalization immunotherapy hypoxia |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1245708/full |
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