Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages
Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages
复制标题
免疫检查点抑制克服 ADCP 诱导的巨噬细胞免疫抑制。
DOI：
10.1016/j.cell.2018.09.007
复制
发表时间：
2018-10-04
期刊：
影响因子：
64.5
通讯作者：
Song, Erwei
中科院分区：
文献类型：
--
作者：
Su, Shicheng;Zhao, Jinghua;Song, Erwei
抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞吞噬作用（ADCP）对抗肿瘤治疗性抗体的功效起关键作用。我们在这里报告了一个意想不到的发现，ADCP后的巨噬细胞抑制NK细胞介导的ADCC和T细胞介导的细胞毒性在乳腺癌和淋巴瘤。在机制上，AIM 2在ADCP后通过Fc γ R信号传导被募集到吞噬体，并通过经破坏的吞噬体膜感测吞噬的肿瘤DNA而被激活，其随后上调PD-L1和IDO并引起免疫抑制。抗HER 2抗体与PD-L1和IDO抑制剂的联合治疗增强了小鼠模型中的抗肿瘤免疫力和抗HER 2治疗功效。此外，新辅助曲妥珠单抗治疗显著上调HER 2（+）乳腺癌患者肿瘤相关巨噬细胞（TAM）中的PD-L1和IDO，与曲妥珠单抗应答差相关。总的来说，我们的研究结果揭示了ADCP巨噬细胞在癌症免疫抑制中的有害作用，并表明治疗性抗体加免疫检查点阻断可以在癌症治疗中提供协同作用。
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 Fc gamma R 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.