对患有晚期黑素瘤的29人的一项研究发现，易普利姆玛这种药物可能通过耗尽调节性t细胞发挥作用，特别是对于表现出了CD68+CD16+肿瘤渗透巨噬细胞丰富性的人们，这一发现可能有助于使用免疫系统瞄准癌细胞的疗法的设计。
mAbs 直接抑制免疫受体是一种非常有前途的免疫治疗剂。这项研究表明易普利姆玛的潜在作用机制(一个完全是人反细胞毒素的 T 淋巴细胞联合的抗原4),由FcγRIIIA(CD16)表达模单核细胞杀死来自体内的细胞毒性介导的调节性T细胞。值得注意的是,在基线,应答患者显示模的频率明显高于周边单核细胞和t CD68 + CD16 +巨噬细胞的选择性富集与非应答患者相比。如果进一步证实,这些发现可能有助于预测生物标志物的生成面板、抗体设计和合理的联合疗法的发展促进抗肿瘤免疫力。
原文链接：Ipilimumab-dependent Cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients
原文摘要：Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4–specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14++CD16- monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68+/CD163+ macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti–CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.
