Role of NKG2D, DNAM-1 and natural cytotoxicity receptors in cytotoxicity toward rhabdomyosarcoma cell lines mediated by resting and IL-15-activated human natural killer cells
Role of NKG2D, DNAM-1 and natural cytotoxicity receptors in cytotoxicity toward rhabdomyosarcoma cell lines mediated by resting and IL-15-activated human natural killer cells
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DOI：
10.1007/s00262-015-1657-9
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发表时间：
2015-05-01
影响因子：
5.8
通讯作者：
van Tol, Maarten J. D.
中科院分区：
文献类型：
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作者：
Boerman, Gerharda H.;van Ostaijen-ten Dam, Monique M.;van Tol, Maarten J. D.
晚期（复发/难治性和IV期）横纹肌肉瘤（RMS）的儿童预后不良，尽管进行了强化化疗和自体干细胞抢救，5年生存率为5 - 35%。开发新的、额外的治疗方式对提高生存率是必要的。在这项临床前研究中，我们研究了静息和精氨酸激活的自然杀伤（NK）细胞裂解RMS细胞系的潜力，以及所涉及的途径，以探索（激活的）NK细胞免疫疗法的最终临床应用。RMS细胞系（n = 3来源于胚胎RMS和n = 2来源于肺泡RMS）对静息NK细胞介导的细胞溶解敏感，使用IL-15激活的NK细胞可显著增加这种敏感性。流式细胞术和细胞溶解试验用于确定参与识别和溶解RMS细胞的NK细胞的激活和抑制途径。NKG 2D和DNAM-1受体-配体相互作用对于静息NK细胞的细胞溶解至关重要，因为同时阻断这两种途径会导致细胞毒性几乎完全消除。相反，DNAM-1和NKG 2D的联合阻断仅导致IL-15激活的NK细胞的溶解活性的部分降低。在这方面，残留的溶解，至少部分，介导的途径涉及天然细胞毒性受体NKp 30和NKp 46。这些发现支持进一步探索基于NK细胞的免疫疗法作为RMS当前治疗策略的辅助方式。
Children with advanced stages (relapsed/refractory and stage IV) of rhabdomyosarcoma (RMS) have a poor prognosis despite intensive chemotherapy and autologous stem cell rescue, with 5-year survival rates ranging from 5 to 35 %. Development of new, additional treatment modalities is necessary to improve the survival rate. In this preclinical study, we investigated the potential of resting and cytokine-activated natural killer (NK) cells to lyse RMS cell lines, as well as the pathways involved, to explore the eventual clinical application of (activated) NK cell immunotherapy. RMS cell lines (n = 3 derived from embryonal RMS and n = 2 derived from alveolar RMS) were susceptible to cytolysis mediated by resting NK cells, and this susceptibility was significantly increased using IL-15-activated NK cells. Flow cytometry and cytolytic assays were used to define the activating and inhibitory pathways of NK cells involved in recognizing and lysing RMS cells. NKG2D and DNAM-1 receptor-ligand interactions were essential in cytolysis by resting NK cells, as simultaneous blocking of both pathways resulted in almost complete abrogation of the cytotoxicity. In contrast, combined blocking of DNAM-1 and NKG2D only led to partial reduction of the lytic activity of IL-15-activated NK cells. In this respect, residual lysis was, at least partly, mediated by pathways involving the natural cytotoxicity receptors NKp30 and NKp46. These findings support further exploration of NK cell-based immunotherapy as adjuvant modality in current treatment strategies of RMS.