A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer
The anticancer effects of immune checkpoint inhibitors (ICIs) have been widely examined recently. Although ICIs have been progressively improved for successful gastric cancer treatment, different trials of ICIs such as pembrolizumab and nivolumab have yielded widely variable response rates. Strategi...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770521001753 |
| _version_ | 1819283413580906496 |
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| author | Nan Hu Wei Li Yidong Hong Zengtao Zeng Jingzhou Zhang Xueyu Wu Kangjie Zhou Fenglei Wu |
| author_facet | Nan Hu Wei Li Yidong Hong Zengtao Zeng Jingzhou Zhang Xueyu Wu Kangjie Zhou Fenglei Wu |
| author_sort | Nan Hu |
| collection | DOAJ |
| description | The anticancer effects of immune checkpoint inhibitors (ICIs) have been widely examined recently. Although ICIs have been progressively improved for successful gastric cancer treatment, different trials of ICIs such as pembrolizumab and nivolumab have yielded widely variable response rates. Strategies to further improve the efficacy of ICIs are still needed. Previous studies have shown that de novo DNA methylation is acquired by PD1+CD8+ tumor-infiltrating T cells (TILs), which cause a hierarchical downregulation of cytokines such as interferon-γ (IFN-γ). The epigenetic agent 5-Aza-2′-deoxycytidine (DAC) blocks de novo DNA methylation in activated PD1+CD8+ TILs. Such a feature might help enhance the anti-tumor effect of immune checkpoint blockade (ICB) treatment. In this study, polyethylene glycol-poly(ε-caprolactone) (PEG-PCL) nanoparticles (NPs) were linked to the anti-programmed death-1 monoclonal antibody nivolumab to yield αPD1-NPs for targeting TILs with PD1 overexpression using DAC. In addition, the NPs increased DAC stability and improved IFN-γ secretion and the anti-tumor effect of ICB in vitro. Therefore, targeted delivery of DAC reverses the exhaustion of PD1+CD8+ TILs and improves T cell responses and the treatment effect of ICB. These findings suggest that nivolumab-NPs are a potential tool for the delivery of epigenetic drugs, which could enhance the anti-tumor effect of ICB in gastric cancer. |
| first_indexed | 2024-12-24T01:31:05Z |
| format | Article |
| id | doaj.art-52ac744cc5184519bdbbb8393446d0c5 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-24T01:31:05Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-52ac744cc5184519bdbbb8393446d0c52022-12-21T17:22:21ZengElsevierMolecular Therapy: Oncolytics2372-77052022-03-0124148159A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancerNan Hu0Wei Li1Yidong Hong2Zengtao Zeng3Jingzhou Zhang4Xueyu Wu5Kangjie Zhou6Fenglei Wu7Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaCenter of Research Laboratory, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaDepartment of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaDepartment of General Surgery, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaDepartment of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaDepartment of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaDepartment of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, ChinaDepartment of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, China; Corresponding author Fenglei Wu, Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu 222000, China.The anticancer effects of immune checkpoint inhibitors (ICIs) have been widely examined recently. Although ICIs have been progressively improved for successful gastric cancer treatment, different trials of ICIs such as pembrolizumab and nivolumab have yielded widely variable response rates. Strategies to further improve the efficacy of ICIs are still needed. Previous studies have shown that de novo DNA methylation is acquired by PD1+CD8+ tumor-infiltrating T cells (TILs), which cause a hierarchical downregulation of cytokines such as interferon-γ (IFN-γ). The epigenetic agent 5-Aza-2′-deoxycytidine (DAC) blocks de novo DNA methylation in activated PD1+CD8+ TILs. Such a feature might help enhance the anti-tumor effect of immune checkpoint blockade (ICB) treatment. In this study, polyethylene glycol-poly(ε-caprolactone) (PEG-PCL) nanoparticles (NPs) were linked to the anti-programmed death-1 monoclonal antibody nivolumab to yield αPD1-NPs for targeting TILs with PD1 overexpression using DAC. In addition, the NPs increased DAC stability and improved IFN-γ secretion and the anti-tumor effect of ICB in vitro. Therefore, targeted delivery of DAC reverses the exhaustion of PD1+CD8+ TILs and improves T cell responses and the treatment effect of ICB. These findings suggest that nivolumab-NPs are a potential tool for the delivery of epigenetic drugs, which could enhance the anti-tumor effect of ICB in gastric cancer.http://www.sciencedirect.com/science/article/pii/S2372770521001753PD1nano-delivery systemepigenetic alterationT cell immune responsegastric cancer |
| spellingShingle | Nan Hu Wei Li Yidong Hong Zengtao Zeng Jingzhou Zhang Xueyu Wu Kangjie Zhou Fenglei Wu A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer Molecular Therapy: Oncolytics PD1 nano-delivery system epigenetic alteration T cell immune response gastric cancer |
| title | A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer |
| title_full | A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer |
| title_fullStr | A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer |
| title_full_unstemmed | A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer |
| title_short | A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer |
| title_sort | pd1 targeted nano delivery system based on epigenetic alterations of t cell responses in the treatment of gastric cancer |
| topic | PD1 nano-delivery system epigenetic alteration T cell immune response gastric cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2372770521001753 |
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