Platinum-Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment
Platinum-Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment
复制标题
基于铂的 TREM2 抑制剂通过重塑免疫抑制微环境来抑制肿瘤
DOI：
10.1002/anie.202213337
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发表时间：
2022-12-07
影响因子：
16.6
通讯作者：
Wang, Xiaoyong
中科院分区：
文献类型：
--
作者：
Yang, Tao;Zhang, Shuren;Wang, Xiaoyong
髓样细胞上表达的触发受体-2(TREM2)是肿瘤浸润性巨噬细胞的重要促肿瘤标志物，在肿瘤微环境中显示出强大的免疫抑制活性。从奥沙利铂(OP)和青蒿琥酯(ART)衍生的铂(IV)络合物OPA在体内外对人结肠癌细胞具有直接的细胞毒作用，并具有抑制巨噬细胞TREM2的免疫调节活性。此外，OPA还通过减少CD206(+)和Cx(3)CR1(+)免疫抑制巨噬细胞的数量，抑制了MC38结直肠癌小鼠模型的肿瘤生长，并促进了免疫刺激树突状细胞、细胞毒T细胞和自然杀伤细胞的扩张和渗透。OPA是第一个小分子TREM2抑制剂，能够缓解免疫抑制的肿瘤微环境，提高铂类药物的化学抗癌效率，从而显示出典型的化学免疫治疗药物的特征。
Triggering receptor expressed on myeloid cells-2 (TREM2) is a key pro-tumorigenic marker of tumor-infiltrating macrophages, showing potent immunosuppressive activity in tumor microenvironment. A platinum(IV) complex OPA derived from oxaliplatin (OP) and artesunate (ART) exhibited direct cytotoxicity against human colon cancer cells and immunomodulatory activity to inhibit TREM2 on macrophages in vitro and vivo. Furthermore, OPA deterred the tumor growth in mouse models bearing MC38 colorectal tumor by reducing the number of CD206(+) and CX(3)CR1(+) immunosuppressive macrophages; it also promoted the expansion and infiltration of immunostimulatory dendritic, cytotoxic T, and natural killer cells. OPA is the first small-molecular TREM2 inhibitor capable of relieving immunosuppressive tumor microenvironment and enhancing chemical anticancer efficiency of a platinum drug, thus showing typical characteristics of a chemoimmunotherapeutic agent.