免疫检查点抑制克服了巨细胞诱导的免疫抑制
Shicheng Su1, Jinghua Zhao1, Yue Xing1
1Guangdong 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
|October 6, 2018
概括
巨细胞的抗体依赖性细胞化 (ADCP) 意外地抑制了抗瘤免疫力. 与治疗抗体一起向PD- L1和IDO可以增强抗癌效果.
科学领域:
- 免疫学
- 癌症学
- 癌症治疗
背景情况:
- 抗体依赖性细胞毒性 (ADCC) 和细胞化 (ADCP) 是治疗癌症抗体的关键机制.
- 在调节瘤微环境方面,ADCP的确切作用尚不完全理解.
研究的目的:
- 研究ADCP对免疫细胞介导的抗瘤反应的影响.
- 阐明ADCP影响瘤微环境的分子机制.
- 探索结合疗法以提高抗癌疗效.
主要方法:
- 在乳腺癌和淋巴瘤模型中研究了ADCP.
- 使用了FcγR信号,AIM2炎症酶激活和体完整性测试.
- 评估了巨细胞中PD-L1和IDO的上调.
- 在小鼠模型中评估了用抗HER2抗体和PD- L1/ IDO抑制剂的联合治疗.
- 在接受新辅助特拉斯图祖马布的HER2+乳腺癌患者中分析了瘤相关的巨细胞.
主要成果:
- 通过ADCP调解的巨被发现可以抑制NK细胞调解的ADCC和T细胞毒性.
- 由细胞化瘤DNA触发的AIM2炎症酶激活,可提高PD-L1和IDO的调节,从而导致免疫抑制.
- 用抗HER2抗体和PD- L1/ IDO抑制剂的联合治疗改善了小鼠的抗瘤免疫力和治疗效果.
- 在TAM患者中,trastuzumab治疗与PD- L1和IDO增加以及治疗反应较差相关.
结论:
- 在癌症免疫抑制中,ADCP介导的巨细胞起着有害的作用.
- 将PD-L1和IDO与治疗抗体结合为协同抗瘤效应提供了一个有希望的策略.
- 这些发现凸显了结合抗体治疗和免疫检查点阻塞的潜力,以改善癌症治疗结果.
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