Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, 94805 Villejuif, France. Department of Pediatric Oncology, GRCC, 94805 Villejuif, France. University of Paris Sud XI, 94805 Villejuif, France. Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France. INSERM U1138, 94805 Villejuif, France.
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, 94805 Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer, CICBT507, GRCC, 94805 Villejuif, France.
Sci Transl Med. 2015 Apr 15;7(283):283ra55. doi: 10.1126/scitranslmed.aaa2327.
The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P < 0.001), adding prognostic value to known risk factors such as N-Myc amplification and age >18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification.
免疫监视机制控制高危神经母细胞瘤（HR-NB），一种主要的儿科恶性肿瘤，一直难以捉摸。我们确定了自然杀伤（NK）细胞的潜在作用，特别是 NK 受体 NKp30 与其配体 B7-H6 之间的相互作用，在骨髓清除性多模式化疗和干细胞移植后 HR-NB 的转移进展和存活中的作用。表达 NKp30 配体 B7-H6 的 NB 细胞以 NKp30 依赖的方式刺激 NK 细胞。可溶性 B7-H6 的血清浓度与 NKp30 的下调、骨髓转移和化疗耐药性相关，并且 HR-NB 患者血清中的可溶性 B7-H6 抑制了体外 NK 细胞的功能。影响 NK 细胞功能极化的不同 NKp30 同工型的表达与三个独立的 HR-NB 缓解期诱导化疗后转移的 10 年无事件生存队列相关（n=196，P<0.001），除了已知的风险因素如 N-Myc 扩增和年龄>18 个月之外，增加了预后价值。我们得出结论，NKp30 和 B7-H6 之间的相互作用可能导致 NB 患者的命运，并且循环 NK 细胞上 NKp30 同工型的表达和血清中可溶性 B7-H6 的浓度都可能作为风险分层的生物标志物具有临床意义。
