Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients
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DOI：
10.1073/pnas.1417320112
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发表时间：
2015-05-12
影响因子：
11.1
通讯作者：
Speiser, Daniel E.
中科院分区：
文献类型：
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作者：
Romano, Emanuela;Kusio-Kobialka, Monika;Speiser, Daniel E.
用针对抑制性免疫受体的免疫调节性单克隆抗体增强免疫应答是癌症治疗中有前途的方式。已经证明了阻断抑制性免疫检查点的抗体（如细胞毒性T淋巴细胞相关抗原4（CTLA-4）或PD-1/PD-L1）的临床疗效。用伊匹单抗（一种完全人CTLA-4特异性mAb）治疗在转移性黑色素瘤中显示出持久的临床疗效;然而，其作用机制仅被部分理解。这是一项对29例接受伊匹单抗治疗的晚期皮肤黑色素瘤患者的研究。我们通过流式细胞术、抗体依赖性细胞介导的细胞毒性（ADCC）测定和免疫组织化学分析了15例对伊匹单抗有反应和14例无反应的患者的外周血单核细胞（PBMC）和匹配的黑色素瘤转移。PBMC和匹配的肿瘤活组织检查在给药前24小时收集（即，基线）和ipilimumab后长达4周。据我们所知，我们的研究结果首次表明，易普利姆玛可以与表达Fc γ RIIIA（CD 16）的非经典单核细胞体外结合，导致ADCC介导的调节性T细胞（TcB）裂解。相反，经典的CD 14（++）CD 16（-）单核细胞不能这样做。此外，我们发现，与无应答患者相比，易普利姆玛应答患者显示出显著更高的非经典单核细胞的基线外周频率。在肿瘤微环境中，应答者在基线时具有更高的CD 68（+）/CD 163（+）巨噬细胞比率，并且在治疗后显示Treg浸润减少。总之，我们的研究结果表明，抗CTLA-4治疗可以靶向体内TcB。然而，需要进行更大规模的转化研究来证实易普利姆玛在患者中的这种作用机制。
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 Fc gamma RIIIA (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.