Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Cell. 2018 Oct 4;175(2):442-457.e23. doi: 10.1016/j.cell.2018.09.007.
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.
抗体依赖的细胞细胞毒性 (ADCC) 和抗体依赖的细胞吞噬作用 (ADCP) 对肿瘤治疗性抗体的疗效起着至关重要的作用。我们在这里报告了一个意外的发现，即 ADCP 后的巨噬细胞会抑制乳腺癌和淋巴瘤中 NK 细胞介导的 ADCC 和 T 细胞介导的细胞毒性。从机制上讲，AIM2 在 ADCP 后通过 FcγR 信号被招募到吞噬体，并通过被破坏的吞噬体膜感应吞噬的肿瘤 DNA 而被激活，随后上调 PD-L1 和 IDO 并引起免疫抑制。在小鼠模型中，联合使用抗 HER2 抗体和 PD-L1 和 IDO 的抑制剂可增强抗肿瘤免疫和抗 HER2 治疗效果。此外，新辅助曲妥珠单抗治疗可显著上调 HER2 乳腺癌患者肿瘤相关巨噬细胞 (TAMs) 中的 PD-L1 和 IDO，与曲妥珠单抗反应不良相关。总之，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能在癌症治疗中具有协同作用。
