Platinum‐Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment. (7th December 2022)

• Record Type: Journal Article
• Authors: Yang, Tao; Zhang, Shuren; Yuan, Hao; Wang, Ying; Cai, Linxiang; Chen, Hanhua; Wang, Xiaoyu; Song, Dongfan; Wang, Xiaohui; Guo, Zijian; Wang, Xiaoyong
• Is Part Of: Angewandte Chemie. Volume 135:Number 2(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-07
• Subjects: chemoimmunotherapeutic agent -- immunosuppression -- platinum drug -- tumor microenvironment -- TREM2 inhibitor; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202213337
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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 CX3 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. Abstract : Platinum complex OPA shows a potent chemoimmunotherapeutic effect on tumors by impeding DNA replication and inhibiting the triggering receptor expressed on myeloid cells‐2 (TREM2). OPA promotes the polarization of macrophages from immunosuppressive M2 to tumoricidal M1 phenotype, and stimulates dendritic, cytotoxic T, and natural killer cells to restrain cancer cells. By transforming the tumor microenvironment, OPA overcomes the tumor resistance to platinum drugs.