Lv Mengmeng, Guo Sheng, Zhang Xinyu, Zou Yan, Chen Qiang, Zang Chongyi, Huang Shuo, Hu Yuhan, Wang Yanling, Wang Qianqing, Zhong Jiateng
Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Department of Pathology, Xinxiang Medical University, Xinxiang, Henan, China.
Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China, Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China.
Int Immunopharmacol. 2023 Nov;124(Pt A):110918. doi: 10.1016/j.intimp.2023.110918. Epub 2023 Sep 12.
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.
免疫疗法在恶性肿瘤治疗方面取得了重大进展。然而，由于免疫疗法的低应答率和独特的毒性特征，以及一些初始应答者随后出现获得性耐药，将免疫疗法与抗癌药物联合使用的策略引起了广泛关注。EZH2是一种多梳抑制复合物的组蛋白甲基转移酶亚基，在多种肿瘤中高表达，靶向EZH2已成为肿瘤治疗和药物联合的新策略。在此，我们研究了EZH2抑制剂对结肠癌细胞的作用及其与免疫疗法的联合应用。我们的结果表明，EZH2抑制剂不仅能显著抑制结肠直肠癌（CRC）细胞的存活并诱导凋亡，有效抑制细胞侵袭和迁移，还能使细胞表面PD-L1受体的表达增加。为了确定EZH2与免疫疗法联合的效果，我们将EZH2抑制剂与减毒沙门氏菌递送的PD-1 siRNA联合使用。体内实验表明，EZH2抑制剂与沙门氏菌递送的PD-1 siRNA联合使用可进一步抑制CRC的发展，触发有效的抗肿瘤免疫，并提高治疗效果。其潜在机制主要涉及协同免疫调节和凋亡。本研究提出了一种基于EZH2抑制剂与基于PD-1抑制的免疫疗法联合的新策略。
