Centipeda minima 和 6-O-angeloyplelenolin 增强免疫检查点抑制剂在非小细胞肺癌中的疗效。
Centipeda minima and 6-O-angeloylplenolin enhance the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.
发表日期：2024 Jun 13
作者：
Min Wang, Hua Guo, Bei-Bei Sun, Xiao-Liang Jie, Xue-Yan Shi, Yong-Qiang Liu, Xu-Liu Shi, Li-Qin Ding, Peng-Hui Xue, Feng Qiu, Wei Cao, Gui-Zhen Wang, Guang-Biao Zhou
来源：
PHYTOMEDICINE
摘要：
化疗药物包括顺铂、吉西他滨和培美曲塞，通过增加 PD-L1 表达和增强 T 细胞的细胞毒性，显着增强免疫检查点抑制剂 (ICIs) 在非小细胞肺癌 (NSCLC) 中的疗效。然而，低反应率和不良反应限制了化疗/ICI组合在患者中的应用。我们筛选了在抗PD-L1抗体存在的情况下可以扰乱PD-L1表达并增强T细胞细胞毒性的草药，并进行了研究我们发现，在抗 PD-L1 抗体存在下，小蜈蚣 (CM) 的水提取物显着增强癌细胞杀伤活性和 CD8 T 细胞的颗粒酶 B 表达水平。 CM 及其活性成分 6-O-当归素 (6-OAP) 均通过抑制 GSK-3β-β-TRCP 介导的泛素化和降解来上调 PD-L1 表达。 CM 和 6-OAP 显着增强 ICI 诱导的肿瘤负荷减少和携带 NSCLC 细胞的小鼠总生存期的延长，同时伴有 PD-L1 的上调和 CD8 T 细胞浸润的增加。 CM 还在细胞和患者来源的异种移植小鼠模型中表现出抗 NSCLC 活性。这些数据表明，PD-L1 的诱导表达和 CD8 T 细胞细胞毒性的增强是富含 6-OAP 的 CM 对 NSCLC 的有益作用的基础，提供临床可用且安全的草药，与 ICI 联合使用来治疗这种致命疾病。版权所有 © 2024 Elsevier GmbH。版权所有。
Chemotherapeutic agents including cisplatin, gemcitabine, and pemetrexed, significantly enhance the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) by increasing PD-L1 expression and potentiating T cell cytotoxicity. However, the low response rate and adverse effects limit the application of chemotherapy/ICI combinations in patients.We screened for medicinal herbs that could perturb PD-L1 expression and enhance T cell cytotoxicity in the presence of anti-PD-L1 antibody, and investigated the underlying mechanisms.We found that the aqueous extracts of Centipeda minima (CM) significantly enhanced the cancer cell-killing activity and granzyme B expression level of CD8+ T cells, in the presence of anti-PD-L1 antibody. Both CM and its active component 6-O-angeloylplenolin (6-OAP) upregulated PD-L1 expression by suppressing GSK-3β-β-TRCP-mediated ubiquitination and degradation. CM and 6-OAP significantly enhanced ICI-induced reduction of tumor burden and prolongation of overall survival of mice bearing NSCLC cells, accompanied by upregulation of PD-L1 and increase of CD8+ T cell infiltration. CM also exhibited anti-NSCLC activity in cells and in a patient-derived xenograft mouse model.These data demonstrated that the induced expression of PD-L1 and enhancement of CD8+ T cell cytotoxicity underlay the beneficial effects of 6-OAP-rich CM in NSCLCs, providing a clinically available and safe medicinal herb for combined use with ICIs to treat this deadly disease.Copyright © 2024 Elsevier GmbH. All rights reserved.