Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies
Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies
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DOI：
10.1182/blood-2013-08-519199
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发表时间：
2014-01-30
期刊：
影响因子：
20.3
通讯作者：
Andre, Pascale
中科院分区：
文献类型：
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作者：
Kohrt, Holbrook E.;Thielens, Ariane;Andre, Pascale
当利妥昔单抗（一种用于治疗B细胞淋巴瘤患者的抗CD20单克隆抗体（mAb））触发时，自然杀伤（NK）细胞通过自发细胞毒性和抗体依赖性细胞介导的细胞毒性（ADCC）介导抗淋巴瘤活性。抑制和激活信号的平衡通过自发细胞毒性决定NK细胞功效的大小。在这里，使用一个嗜酸性细胞免疫球蛋白样受体（KIR）转基因小鼠模型，我们表明，阻断接口的抑制性KIR与主要组织相容性复合体（MHC）I类抗原的淋巴瘤细胞上的抗KIR抗体，防止了致耐受性的相互作用，增强NK细胞的自发细胞毒性。在KIR转基因和同基因鼠淋巴瘤模型中，抗KIR治疗与抗CD20 mAb联合诱导增强的NK细胞介导的利妥昔单抗依赖性体外和体内淋巴瘤细胞毒性。这些结果支持利妥昔单抗和KIR阻断剂联合使用的治疗策略，说明了肿瘤靶向治疗与NK细胞激动剂联合使用的潜在疗效，从而刺激了postrituximab抗淋巴瘤免疫应答。
Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK-cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in KIR transgenic and syngeneic murine lymphoma models. These results support a therapeutic strategy of combination rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor-targeting therapy with an NK-cell agonist, thus stimulating the postrituximab antilymphoma immune response.