Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator
The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy, despite considerable success in anti-tumor immunotherapy. The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy. We hyp...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383522003240 |
| _version_ | 1797740861142859776 |
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| author | Qingqing Xiao Xiaotong Li Chang Liu Yuxin Jiang Yonglong He Wanting Zhang Helena S. Azevedo Wei Wu Yuanzheng Xia Wei He |
| author_facet | Qingqing Xiao Xiaotong Li Chang Liu Yuxin Jiang Yonglong He Wanting Zhang Helena S. Azevedo Wei Wu Yuanzheng Xia Wei He |
| author_sort | Qingqing Xiao |
| collection | DOAJ |
| description | The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy, despite considerable success in anti-tumor immunotherapy. The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy. We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response. Herein, a targeted diterpenoid derivative was integrated with the checkpoint blockade (anti-CTLA-4) to improve immunotherapy using thermosensitive liposomes as carriers. In vivo, the liposomes enabled the co-delivery of the two drug payloads into the tumor. Consequently, the regulatory T cell proliferation was restrained, the cytotoxic T cell infiltration was enhanced, and the profound immunotherapeutic effect was achieved. In addition, the immunotherapeutic effect of another clinically used checkpoint antibody, anti-PD-1, also benefited from the diterpenoid derivative. Of note, our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction. Collectively, co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy. We first time discovered that THBS1 suppression could strengthen checkpoint therapy. |
| first_indexed | 2024-03-12T14:18:33Z |
| format | Article |
| id | doaj.art-8936e5ce255244aabbce7d23133f79ca |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-12T14:18:33Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-8936e5ce255244aabbce7d23133f79ca2023-08-20T04:37:46ZengElsevierActa Pharmaceutica Sinica B2211-38352023-08-0113835033517Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulatorQingqing Xiao0Xiaotong Li1Chang Liu2Yuxin Jiang3Yonglong He4Wanting Zhang5Helena S. Azevedo6Wei Wu7Yuanzheng Xia8Wei He9School of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Engineering and Materials Science, Institute of Bioengineering, Queen Mary University of London, London E1 4NS, UKSchool of Pharmacy, Fudan University, Shanghai 201203, ChinaJiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors.School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Corresponding authors.The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy, despite considerable success in anti-tumor immunotherapy. The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy. We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response. Herein, a targeted diterpenoid derivative was integrated with the checkpoint blockade (anti-CTLA-4) to improve immunotherapy using thermosensitive liposomes as carriers. In vivo, the liposomes enabled the co-delivery of the two drug payloads into the tumor. Consequently, the regulatory T cell proliferation was restrained, the cytotoxic T cell infiltration was enhanced, and the profound immunotherapeutic effect was achieved. In addition, the immunotherapeutic effect of another clinically used checkpoint antibody, anti-PD-1, also benefited from the diterpenoid derivative. Of note, our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction. Collectively, co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy. We first time discovered that THBS1 suppression could strengthen checkpoint therapy.http://www.sciencedirect.com/science/article/pii/S2211383522003240ImmunotherapyDiterpenoid-based conjugateCheckpoint blockadeThrombospondin-1Co-deliveryLiposomes |
| spellingShingle | Qingqing Xiao Xiaotong Li Chang Liu Yuxin Jiang Yonglong He Wanting Zhang Helena S. Azevedo Wei Wu Yuanzheng Xia Wei He Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator Acta Pharmaceutica Sinica B Immunotherapy Diterpenoid-based conjugate Checkpoint blockade Thrombospondin-1 Co-delivery Liposomes |
| title | Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator |
| title_full | Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator |
| title_fullStr | Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator |
| title_full_unstemmed | Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator |
| title_short | Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator |
| title_sort | improving cancer immunotherapy via co delivering checkpoint blockade and thrombospondin 1 downregulator |
| topic | Immunotherapy Diterpenoid-based conjugate Checkpoint blockade Thrombospondin-1 Co-delivery Liposomes |
| url | http://www.sciencedirect.com/science/article/pii/S2211383522003240 |
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