低风险妊娠滋养细胞肿瘤（GTN）目前正在接受单一化疗作为一线治疗。如果出现耐药性，建议采用二线单一化疗或多化疗。作为这些有毒且历史悠久的化疗药物的替代方案，抗 PD-L1 单克隆抗体 (avelumab) 的疗效在 TROPHIMMUN II 期试验队列 A 中进行了评估。Avelumab 的治愈率达到 53%，且耐受性可接受，包括正常进一步妊娠和分娩。除了阻断 PD-1/PD-L1 相互作用之外，avelumab 的作用还可能依赖于表达 FcγR3A 的自然杀伤 (NK) 细胞介导的抗体依赖性细胞介导的细胞毒性 (ADCC) 的诱导。这项转化研究旨在测试是否ADCC 参与 avelumab 对 GTN 的疗效，并且 FcγR3A 亲和力多态性是否有助于预测 GTN 对 avelumab 的反应。通过转录组和蛋白质组分析验证了肿瘤的 PD-L1 表达和浸润 GTN 的 NK 细胞的表型。然后，在存在和不存在 avelumab 的情况下将 JEG-3 绒毛膜癌细胞与人 NK 细胞共培养。评估 FcγR3A 功能多态性对 NK 细胞活化状态和 JEG-3 绒毛膜癌细胞活力的影响。最后，重新分析 TROPHIMMUN 试验的数据，以确定患者 FcγR3A 多态性对其对 avelumab 反应的影响。我们证实 FcγR3A NK 细胞浸润表达 PD-L1 的 GTN。在体外，avelumab 包被的 JEG-3 绒毛膜癌细胞诱导 NK 细胞活化，从而促进 JEG-3 细胞的破坏。当 avelumab 的 Fc 部分被去除时，NK 细胞激活被消除，这证明了 Fcγ 受体在此过程中的重要性。使用这种 ADCC 模型，我们证明 NK 细胞上的高亲和力 FcγR3A 多态性与 avelumab 更好的体外反应相关。与这一结果一致，来自 TROPHIMMUN 试验的高亲和力 FcγR3A 多态性纯合子的患者对 avelumab 具有更好的临床反应。我们的工作表明，ADCC 有助于 avelumab 在 GTN 中的治疗效果，并且个体患者的反应受到 FcγR3A 的影响多态性。 FcγR3A 多态性可用作生物标志物，以识别诊断为单一化疗耐药性 GTN 的患者最有可能对 avelumab 产生反应。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Low-risk gestational trophoblastic neoplasia (GTN) are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line mono- or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by FcγR3A-expressing natural killer (NK) cells.This translational study aimed at testing whether ADCC is involved in avelumab efficacy on GTN and if FcγR3A affinity polymorphism could help predicting the response to avelumab in GTN.The expression of PD-L1 by the tumor and the phenotype of NK cells infiltrating GTN were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human NK cells in presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of NK cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were reanalyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab.We confirmed that FcγR3A+ NK cells infiltrated PD-L1-expressing GTN. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced NK cell activation, which promoted the destruction of JEG-3 cells. NK cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of ADCC, we demonstrated that high-affinity FcγR3A polymorphism on NK cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high affinity FcγR3A polymorphism had better clinical response to avelumab.Our work demonstrates that ADCC contributes to the therapeutic effect of avelumab in GTN and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant GTN who are most likely to respond to avelumab.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.