Pharmacological manipulation of Ezh2 with Salvianolic acid B results in tumor vascular normalization and synergizes with cisplatin and T cell-mediated immunotherapy.
Pharmacological manipulation of Ezh2 with Salvianolic acid B results in tumor vascular normalization and synergizes with cisplatin and T cell-mediated immunotherapy.
复制标题
DOI：
10.1016/j.phrs.2022.106333
复制
发表时间：
2022-06
影响因子：
9.3
通讯作者：
C. Qian;Chunmei Yang;Yu Tang;Weiwei Zheng;Yueke Zhou;Shan Zhang;Mengyao Song;Peng Cheng
中科院分区：
文献类型：
--
作者：
C. Qian;Chunmei Yang;Yu Tang;Weiwei Zheng;Yueke Zhou;Shan Zhang;Mengyao Song;Peng Cheng
肿瘤血管系统的特征在于异常的结构和功能，通过限制免疫细胞浸润到肿瘤中而导致肿瘤微环境（TME）的免疫抑制特征。肿瘤中的血管灌注缺陷也损害了化疗剂的递送和功效。靶向异常肿瘤血管已成为改善化疗和免疫治疗结果的有效治疗策略。在这项研究中，我们证明，丹参素酸B（SalB），丹参的主要成分之一，引起乳腺癌小鼠模型的血管正常化，有助于改善化疗药物顺铂的输送和反应，以及减弱转移。此外，SalB与抗PD-L1阻断剂的组合延缓了肿瘤生长，这主要是由于免疫效应细胞的浸润增加和抗PD-L1向肿瘤中的递送增强。从机制上讲，肿瘤细胞增强子zeste同源物2（Ezh 2）驱动的细胞因子破坏了内皮连接，减少了VE-钙粘蛋白的表达，这可以在SalB的存在下挽救。SalB通过调节肿瘤细胞与内皮细胞（EC）之间的相互作用来恢复血管完整性，为实现血管正常化提供了主要途径。综上所述，我们的数据阐明了SalB通过触发肿瘤血管正常化来增强肿瘤细胞对化疗和免疫治疗的敏感性，为乳腺癌患者提供了SalB与化疗或免疫治疗相结合的潜在治疗策略。
Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment (TME) through limiting immune cell infiltration into tumors. The defective vascular perfusion in tumors also impairs the delivery and efficacy of chemotherapeutic agents. Targeting abnormal tumor blood vessels has emerged as an effective therapeutic strategy to improve the outcome of chemotherapy and immunotherapy. In this study, we demonstrated that Salvianolic acid B (SalB), one of the major ingredients of Salviamiltiorrizaelicited vascular normalization in the mouse models of breast cancer, contributing to improved delivery and response of chemotherapeutic agent cisplatin as well as attenuated metastasis. Moreover, SalB in combination with anti-PD-L1 blockade retarded tumor growth, which was mainly due to elevated infiltration of immune effector cells and boosted delivery of anti-PD-L1 into tumors. Mechanistically, tumor cell enhancer of zeste homolog 2 (Ezh2)-driven cytokines disrupted the endothelial junctions with diminished VE-cadherin expression, which could be rescued in the presence of SalB. The restored vascular integrity by SalB via modulating the interactions between tumor cells and endothelial cells (ECs) offered a principal route for achieving vascular normalization. Taken together, our data elucidated that SalB enhanced sensitivity of tumor cells to chemotherapy and immunotherapy through triggering tumor vascular normalization, providing a potential therapeutic strategy of combining SalB and chemotherapy or immunotherapy for patients with breast cancer.