Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator  

作　　者：Qingqing Xiao Xiaotong Li Chang Liu Yuxin Jiang Yonglong He Wanting Zhang Helena SAzevedo Wei Wu Yuanzheng Xia Wei He 

机构地区：[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 El 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

出　　处：《Acta Pharmaceutica Sinica B》2023年第8期3503-3517,共15页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81872823,82073782 and 81973524);the Double First-Class(CPU2018PZQ13,China)of the CPU;the Shanghai Science and Technology Committee(19430741500,China);the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine(zdsys-202103);the Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZ202004);Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University),Ministry of Education(GKEKF202010);。

摘　　要：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 thermo sensitive 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.

关 键 词：IMMUNOTHERAPY Diterpenoid-based conjugate Checkpoint blockade Thrombospondin-1 CO-DELIVERY Liposomes 

分 类 号：O62[理学—有机化学]