Anti-EGFR Antibody Cetuximab Enhances the Cytolytic Activity of Natural Killer Cells toward Osteosarcoma
Anti-EGFR Antibody Cetuximab Enhances the Cytolytic Activity of Natural Killer Cells toward Osteosarcoma
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DOI：
10.1158/1078-0432.ccr-11-2277
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发表时间：
2012-01-15
影响因子：
11.5
通讯作者：
Lankester, Arjan C.
中科院分区：
文献类型：
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作者：
Pahl, Jens H. W.;Ruslan, S. Eriaty N.;Lankester, Arjan C.
目的：骨肉瘤和尤文氏肉瘤是儿童青少年最常见的骨肿瘤。尽管进行了密集的化疗，但晚期疾病患者的预后很差，这表明需要替代疗法。肉瘤细胞对静息自然杀伤(NK)细胞的杀伤活性敏感，IL-15刺激可改善NK细胞的杀伤活性。在这项研究中，我们探索是否可以通过抗体依赖的细胞毒性(ADCC)来增强静止的NK细胞的杀细胞功能并特异性地针对肉瘤细胞。实验设计：用流式细胞仪检测表皮生长因子受体(EGFR)在骨肉瘤和尤文氏肉瘤细胞系上的表达，并用免疫组织化学方法检测骨肉瘤活检和切除标本中EGFR的表达。结果：化疗敏感和耐药的骨肉瘤细胞(12/12)、原代培养的骨肉瘤细胞(4/5)、尤文肉瘤细胞系(2/7)均表达EGFR。在西妥昔单抗存在下，静息的NK细胞对所有表达EGFR的肉瘤细胞的杀伤活性显著增加，与IL-15激活的NK细胞的杀伤活性相当。原代骨肉瘤培养物表面EGFR的表达与原发肿瘤中的EGFR表达相关。骨肉瘤患者来源的NK细胞对自体肿瘤细胞的杀伤活性与健康献血者的NK细胞一样有效。结论：西妥昔单抗可以增强静息NK细胞对骨肉瘤细胞的杀伤能力，并将其定向到骨肉瘤细胞。因此，西妥昔单抗介导的免疫治疗可能被认为是治疗晚期骨肉瘤的一种新的治疗方式。临床癌症资源；18(2)；432-41。(C)2011年AACR。
Purpose: Osteosarcoma and Ewing's sarcoma are the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease have a poor prognosis, illustrating the need for alternative therapies. Sarcoma cells are susceptible to the cytolytic activity of resting natural killer (NK) cells which can be improved by interleukin (IL)-15 stimulation. In this study, we explored whether the cytolytic function of resting NK cells can be augmented and specifically directed toward sarcoma cells by antibody-dependent cellular cytotoxicity (ADCC).Experimental Design: Epidermal growth factor receptor (EGFR) expression was examined on osteosarcoma and Ewing's sarcoma cell lines by flow cytometry and in osteosarcoma biopsy and resection specimens by immunohistochemistry. Cetuximab-mediated ADCC by NK cells from osteosarcoma patients and healthy controls was measured with 4-hour (51)Cr release assays.Results: EGFR surface expression was shown on chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cells (12/12), most primary osteosarcoma cultures (4/5), and few Ewing's sarcoma cell lines (2/7). In the presence of cetuximab, the cytolytic activity of resting NK cells against all EGFR-expressing sarcoma cells was substantially increased and comparable with that of IL-15-activated NK cells. Surface EGFR expression on primary osteosarcoma cultures correlated with EGFR expression in the original tumor. The cytolytic activity of osteosarcoma patient-derived NK cells against autologous tumor cells was as efficient as that of NK cells from healthy donors.Conclusion: Our data show that the cytolytic potential of resting NK cells can be potentiated and directed toward osteosarcoma cells with cetuximab. Therefore, cetuximab-mediated immunotherapy may be considered a novel treatment modality in the management of advanced osteosarcoma. Clin Cancer Res; 18(2); 432-41. (C) 2011 AACR.