Anti-myeloma activity and molecular logic operation by Natural Killer cells in microfluidic droplets.
Anti-myeloma activity and molecular logic operation by Natural Killer cells in microfluidic droplets.
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DOI：
10.1016/j.snb.2018.11.068
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
Saheli Sarkar;S. Mckenney;Pooja Sabhachandani;J. Adler;Xiaozhe Hu;Dina Stroopinksy;J. Rosenblatt;D. Avigan;T. Konry
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文献类型：
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作者：
Saheli Sarkar;S. Mckenney;Pooja Sabhachandani;J. Adler;Xiaozhe Hu;Dina Stroopinksy;J. Rosenblatt;D. Avigan;T. Konry
目前正在研究激活自然杀伤 (NK) 细胞等效应淋巴细胞的免疫靶向疗法，用于治疗多发性骨髓瘤 (MM)，这是第二种最常见的血液癌症。然而，单个 NK 细胞的溶细胞潜力具有高度异质性，因此难以在单细胞分辨率下检测、量化和关联动态效应器-靶细胞相互作用的结果。在这里，我们提出了一个微流体生物测定平台，能够基于活性筛选细胞和分子免疫疗法。我们确定了与 NK-MM 细胞相互作用相关的独特功能特征。添加免疫调节药物来那度胺改变了 NK 敏感的 MM 细胞的反应，但没有改变 NK 耐受的 MM 细胞的反应。通过阻断 PD1/PDL1 轴以及用于构建分子逻辑功能（AND 和 NOT 门）的临床相关细胞系 NK92，抗肿瘤细胞毒性显着增加。开发了基于预测剂的数学模型来模拟进展的疾病状态和药物疗效。当前研究的结果验证了这种微流控细胞毒性测定在免疫治疗筛选、生物计算以及未来在精准医学检测患者特异性细胞反应方面的适用性。
Immune-targeted therapies that activate effector lymphocytes such as Natural Killer (NK) cells are currently being investigated for the treatment of Multiple myeloma (MM), the second most common form of hematological cancer. However, individual NK cells are highly heterogeneous in their cytolytic potential, making it difficult to detect, quantify and correlate the outcome of dynamic effector-target cell interactions at single cell resolution. Here, we present a microfluidic bioassay platform capable of activity-based screening of cellular and molecular immunotherapies. We identified distinct functional signatures associated with NK-MM cell interaction. The addition of immunomodulatory drug lenalidomide altered responses of NK-susceptible MM cells but not that of NK-tolerant MM cells. Antitumor cytotoxicity was significantly increased by the blockade of PD1/PDL1 axis as well as the clinically relevant cell line NK92, which were used to construct molecular logic functions (AND and NOT gates). A predictive agent-based mathematical model was developed to simulate progressive disease states and drug efficacy. The findings of the current study validate the applicability of this microfluidic cytotoxicity assay for immunotherapy screening, biocomputation and for future employment in detection of patient-specific cell response for precision medicine.