Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK
Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK
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DOI：
10.1172/jci.insight.130688
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发表时间：
2019-10-17
期刊：
影响因子：
8
通讯作者：
Park, Deric M.
中科院分区：
文献类型：
--
作者：
Giles, Amber J.;Hao, Shuyu;Park, Deric M.
脑膜瘤是最常见的成人中枢神经系统原发肿瘤，但对于复发的脑膜瘤，尤其是世界卫生组织II级和III级肿瘤，目前尚无有效的药物治疗方法。脑膜瘤起源于脑膜，位于血脑屏障之外，因此可直接作为抗体介导的免疫治疗的靶点。我们发现程序性细胞死亡配体1(PD-L1)在多种人类恶性脑膜瘤细胞系和患者肿瘤标本中都有高表达。用抗PD-L1抗体Avelumab靶向PD-L1，诱导自然杀伤细胞在体内外介导表达PD-L1的脑膜瘤的抗体依赖性细胞毒作用(ADCC)。在上调PD-L1表达的靶细胞中，脑膜瘤细胞的ADCC显著增加，反之，在PD-L1缺失的肿瘤细胞中，ADCC显著减少。此外，高亲和力的自然杀伤细胞系HANK在脑膜瘤ADCC中的表现优于健康的供者NK细胞。总之，这些数据支持以Avelumab和Hank细胞靶向PD-L1的临床试验，可能为恶性脑膜瘤患者提供一种新的免疫治疗方法。
Meningiomas are the most common adult primary tumor of the central nervous system, but there are no known effective medical therapies for recurrent meningioma, particularly for World Health Organization grade II and III tumors. Meningiomas arise from the meninges, located outside the blood-brain barrier, and therefore may be directly targeted by antibody-mediated immunotherapy. We found that programmed cell death ligand 1 (PD-L1) was highly expressed in multiple human malignant meningioma cell lines and patient tumor samples. PD-L1 was targeted with the anti-PD-L1 antibody avelumab and directed natural killer cells to mediate antibody-dependent cellular cytotoxicity (ADCC) of PD-L1-expressing meningioma tumors both in vitro and in vivo. ADCC of meningioma cells was significantly increased in target cells that upregulated PD-L1 expression and, conversely, abrogated in tumor cells that were depleted of PD-L1. Additionally, the high-affinity natural killer cell line, haNK, outperformed healthy donor NK cells in meningioma ADCC. Together, these data support a clinical trial designed to target PD-L1 with avelumab and haNK cells, potentially offering a novel immunotherapeutic approach for patients with malignant meningioma.