Ren Shuai, Cai Yiqing, Hu Shunfeng, Liu Jiarui, Zhao Yi, Ding Mengfei, Chen Xiaomin, Zhan Linquan, Zhou Xiangxiang, Wang Xin
Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; School of Medicine, Shandong University, Jinan, Shandong 250012, China.
Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; School of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong 250021, China; Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong 250021, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 251006, China.
Biochem Pharmacol. 2021 Jun;188:114576. doi: 10.1016/j.bcp.2021.114576. Epub 2021 Apr 28.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) with high clinical heterogeneity and poor prognosis. Immune escape mediated by CD47 overexpression contributes to the limited efficacy of rituximab, an anti-CD20 antibody, which indicates a target to improve the efficacy of DLBCL treatment. Here, we validated berberine, a natural compound, as a suppressor of CD47 and revealed the involved mechanism and biological function in DLBCL. Berberine downregulated the expression of CD47 in DLBCL at the transcriptional level by suppressing c-myc expression. Berberine-induced CD47 inhibition enhanced the phagocytosis of macrophages, thereby eliminating DLBCL cells in vitro and in vivo. Interestingly, berberine enhanced the efficiency of anti-CD47 antibody and rituximab-mediated phagocytosis. Moreover, a novel prognostic model based on the combination of CD47 and CD68, a biomarker of macrophages, was established in DLBCL. Our results highlighted for the first time that berberine could restore macrophage function in the tumor microenvironment, enhance rituximab-mediated phagocytosis and promote anti-CD47 antibody function via suppressing CD47 expression, which revealed a new anti-tumor mechanism of berberine and provided novel insights into the rituximab-based immunochemotherapy and CD47-targeted immunotherapy in DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤（NHL）最常见的亚型，具有高度临床异质性和不良预后。CD47过表达介导的免疫逃逸导致抗CD20抗体利妥昔单抗的疗效有限，这表明存在一个可提高DLBCL治疗疗效的靶点。在此，我们验证了天然化合物黄连素是CD47的抑制剂，并揭示了其在DLBCL中的相关机制和生物学功能。黄连素通过抑制c-myc表达在转录水平下调DLBCL中CD47的表达。黄连素诱导的CD47抑制增强了巨噬细胞的吞噬作用，从而在体外和体内消除DLBCL细胞。有趣的是，黄连素提高了抗CD47抗体和利妥昔单抗介导的吞噬作用效率。此外，在DLBCL中建立了一种基于CD47和巨噬细胞生物标志物CD68联合的新型预后模型。我们的结果首次强调，黄连素可通过抑制CD47表达恢复肿瘤微环境中的巨噬细胞功能，增强利妥昔单抗介导的吞噬作用并促进抗CD47抗体功能，这揭示了黄连素新的抗肿瘤机制，并为DLBCL中基于利妥昔单抗的免疫化疗和CD47靶向免疫治疗提供了新的见解。
