抗体依赖性细胞介导的细胞毒性
生物
癌症研究
免疫抑制
免疫系统
抗体
曲妥珠单抗
免疫检查点
细胞毒性
癌症
免疫疗法
免疫学
单克隆抗体
乳腺癌
体外
生物化学
遗传学
作者
Shicheng Su,Jinghua Zhao,Yue Xing,Xiaoqian Zhang,Jiang Liu,Qian Ouyang,Jianing Chen,Fengxi Su,Qiang Liu,Erwei Song
出处
期刊:Cell
[Elsevier]
日期:2018-10-01
卷期号:175 (2): 442-457.e23
被引量:195
标识
DOI:10.1016/j.cell.2018.09.007
摘要
Summary
Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.
科研通智能强力驱动
Strongly Powered by AbleSci AI