免疫疗法
刺
干扰素基因刺激剂
兴奋剂
干扰素
细胞因子
免疫系统
先天免疫系统
医学
癌症研究
癌症免疫疗法
趋化因子
免疫学
体内
药理学
生物
受体
内科学
生物技术
航空航天工程
工程类
作者
Naniye Malli,Travis Monnell,Jahna Soomer-James,Pamela Shaw,Kelly L. Lancaster,Kalli C. Catcott,Melissa Dolan,Rebecca Mosher,Caitlin Routhier,Chen‐Ni Chin,Dorin Toader,Jeremy R. Duvall,Raghida Bukhalid,Timothy B. Lowinger,Marc Damelin
标识
DOI:10.1038/s41467-024-49932-4
摘要
Abstract Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.
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