Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator.
10.1016/j.apsb.2022.07.012
- Author:
Qingqing XIAO
1
;
Xiaotong LI
1
;
Chang LIU
1
;
Yuxin JIANG
1
;
Yonglong HE
1
;
Wanting ZHANG
1
;
Helena S AZEVEDO
2
;
Wei WU
3
;
Yuanzheng XIA
4
;
Wei HE
1
Author Information
1. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
2. School of Engineering and Materials Science, Institute of Bioengineering, Queen Mary University of London, London E1 4NS, UK.
3. School of Pharmacy, Fudan University, Shanghai 201203, China.
4. Jiangsu 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.
- Publication Type:Journal Article
- Keywords:
Checkpoint blockade;
Co-delivery;
Diterpenoid-based conjugate;
Immunotherapy;
Liposomes;
Thrombospondin-1
- From:
Acta Pharmaceutica Sinica B
2023;13(8):3503-3517
- CountryChina
- Language:English
-
Abstract:
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.
