Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions.
Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions.
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DOI：
10.1007/s00262-018-2140-1
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Wieten L
中科院分区：
文献类型：
--
作者：
Mahaweni NM;Bos GMJ;Mitsiades CS;Tilanus MGJ;Wieten L
基于自然杀伤（NK）细胞的免疫疗法是治疗癌症的一种有前途的新方法。然而，NK细胞功能已被证明可能会被肿瘤微环境（TME）中常见的因素所削弱。在这项研究中，我们评估了抗体依赖性细胞介导的细胞毒性（ADCC）和杀伤免疫球蛋白样受体（KIR）配体不匹配的NK细胞的协同潜力，以增强多发性骨髓瘤（MM）中NK细胞的抗肿瘤反应性。选择低氧、乳酸盐、前列腺素E2（PGE 2）或其组合来模拟TME。为了研究这一点，分离了来自健康供体的NK细胞，并在存在TME因子的情况下，在基于流式细胞术的细胞毒性和脱粒（CD 107 a）测定中评估了NK细胞对MM细胞的ADCC响应能力。低氧、乳酸盐和PGE 2降低NK细胞对骨髓瘤靶细胞的细胞毒性。添加达雷妥尤单抗（抗CD 38抗体）增强了NK细胞对高表达CD 38的靶细胞的细胞毒性，但在存在TME的情况下，对CD 38低表达或阴性靶细胞的细胞毒性也没有增强。抑制性KIR和NKG 2A的共染色表明，达雷妥尤单抗增强了所有NK细胞亚群的脱粒。然而，KIR-配体错配的NK细胞是比KIR-配体匹配的NK细胞稍好的效应细胞。总之，我们的研究表明，使用通过触发ADCC来最大化激活NK细胞信号传导的策略与通过选择KIR配体错配供体来最小化抑制性信号传导的方法相结合的组合疗法可以帮助克服NK抑制性TME。这可以作为提高NK细胞临床疗效的平台。本文的在线版本（10.1007/s 00262 -018-2140-1）包含补充材料，可供授权用户使用。
Natural killer (NK) cell-based immunotherapy is a promising novel approach to treat cancer. However, NK cell function has been shown to be potentially diminished by factors common in the tumor microenvironment (TME). In this study, we assessed the synergistic potential of antibody-dependent cell-mediated cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand mismatched NK cells to potentiate NK cell antitumor reactivity in multiple myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were selected to mimic the TME. To investigate this, NK cells from healthy donors were isolated and NK cell ADCC capacity in response to MM cells was assessed in flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK cells against myeloma target cells. The addition of daratumumab (anti-CD38 antibody) augmented NK-cell cytotoxicity against target cells expressing high CD38, but not against CD38 low or negative target cells also in the presence of TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand mismatched NK cells were slightly better effector cells than KIR-ligand matched NK cells. In summary, our study shows that combination therapy using strategies to maximize activating NK cell signaling by triggering ADCC in combination with an approach to minimize inhibitory signaling through a selection of KIR-ligand mismatched donors, can help to overcome the NK-suppressive TME. This can serve as a platform to improve the clinical efficacy of NK cells. The online version of this article (10.1007/s00262-018-2140-1) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Sarkar S;Germeraad WT;Rouschop KM;Steeghs EM;van Gelder M;Bos GM;Wieten L
通讯作者：
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DOI：
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发表时间：
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期刊：
Cancer immunology, immunotherapy : CII
影响因子：
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作者：
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11.5
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20.3
作者：
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影响因子：
20.3
作者：
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通讯作者：
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