减毒沙门氏菌传递的PD-1 siRNA增强了EZH2抑制剂在结直肠癌中的抗肿瘤效应。
Attenuated Salmonella-delivered PD-1 siRNA enhances the antitumor effects of EZH2 inhibitors in colorectal cancer.
发表日期：2023 Sep 12
作者：
Mengmeng Lv, Sheng Guo, Xinyu Zhang, Yan Zou, Qiang Chen, Chongyi Zang, Shuo Huang, Yuhan Hu, Yanling Wang, Qianqing Wang, Jiateng Zhong
来源：
INTERNATIONAL IMMUNOPHARMACOLOGY
摘要：
免疫疗法在恶性肿瘤治疗中取得了显著进展。然而，由于免疫治疗的低响应率和独特的毒性特点以及随后初次反应者产生获得性耐药，将免疫疗法与抗癌药物相结合的策略引起了极大关注。EZH2是一个多聚体组蛋白抑制复合体的组蛋白甲基转移酶亚单位，在各种肿瘤中高度表达，靶向EZH2已成为一种新的肿瘤治疗和药物组合策略。在本研究中，我们研究了EZH2抑制剂对结肠直肠癌细胞的影响以及其与免疫疗法的联合作用。我们的结果表明，EZH2抑制剂不仅可以显著抑制结肠直肠癌（CRC）细胞的存活，诱导细胞凋亡，有效抑制细胞侵袭和迁移，还能导致细胞表面PD-L1受体表达的增加。为了确定EZH2与免疫疗法的联合作用，我们将EZH2抑制剂与通过弱毒沙门菌传递的PD-1 siRNA相结合。体内实验显示，EZH2抑制剂与沙门菌传递的PD-1 siRNA的联合可以进一步抑制CRC的发展，触发有效的抗肿瘤免疫反应，并提高治疗效果。其潜在机制主要涉及协同免疫调节和细胞凋亡。本研究提出了一种基于EZH2抑制剂与基于PD-1抑制的免疫疗法结合的新兴策略。版权所有ⓒ2023 Elsevier B.V. 保留所有权利。
Immunotherapy has made significant progress in the treatment of malignant tumors. However, strategies to combine immunotherapy with anticancer drugs have attracted great attention due to the low response rate and unique toxicity profile of immunotherapies and the subsequent development of acquired resistance in some initial responders. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex,is highly expressed in a variety of tumors, and targeting EZH2 has become a new strategy for tumor therapy and drug combination. Here，we studied the effect of EZH2 inhibitors on colorectal cancer cells and their combination with immunotherapy. Our results demonstrated that EZH2 inhibitors can not only significantly inhibit the survival of colorectal cancer (CRC) cells and induce apoptosis, effectively inhibit cell invasion and migration, but also cause an increase in the expression of PD-L1 receptors on the cell surface. To determine the effect of EZH2 in combination with immunotherapy, we combine EZH2 inhibitors with PD-1 siRNA delivered by attenuated Salmonella. The vivo experiments have shown that the combination of EZH2 inhibitors and Salmonella-delivered PD-1 siRNA can further inhibit the development of CRC, trigger effective anti-tumor immunity, and improve therapeutic efficacy. Its underlying mechanisms mainly involve synergistic immunomodulation and apoptosis. This study suggests an emerging strategy based on a combination of EZH2 inhibitor and immunotherapy based on PD-1 inhibition.Copyright © 2023 Elsevier B.V. All rights reserved.