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 des...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.展开更多
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+4 种基金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)。
文摘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.
