KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma.
KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-09-1720
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Hsu KC
中科院分区：
文献类型：
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作者：
Venstrom JM;Zheng J;Noor N;Danis KE;Yeh AW;Cheung IY;Dupont B;O'Reilly RJ;Cheung NK;Hsu KC
自然杀伤（NK）细胞对神经母细胞瘤表现出细胞毒性。因此，控制NK细胞功能的基因多态性可能影响预后。决定NK细胞反应的两个高度多态性遗传位点编码NK细胞杀伤免疫球蛋白样受体（KIR）及其I类人类白细胞抗原（HLA）配体。我们假设具有“缺失配体”KIR-HLA复合基因型的患者可能从自体造血干细胞移植（HSCT）中获益。169例接受自体造血干细胞移植治疗的4期神经母细胞瘤患者进行了KIR和HLA基因分型。根据患者是否存在HLA配体进行分离，进行自体抑制KIR。对总生存期和无进展生存期进行单因素和多因素分析。64%的患者缺乏一种或多种HLA配体来抑制KIR。与拥有所有HLA配体的患者相比，缺乏HLA配体的患者3年死亡风险降低46% (HR 0.54; 95% CI, 0.35-0.85， P= 0.007)，进展风险降低34% （HR 0.66; 95% CI, 0.44-1.0； P= 0.047）。在所有KIR-HLA组合中，16例缺乏KIR2DL2/2DL3的HLA-C1配体的患者的3年生存率最高，为81% （95% CI: 64-100）。与肿瘤MYCN基因扩增相比，生存与“缺失配体”的相关性更强。KIR-HLA免疫遗传学代表了高风险神经母细胞瘤患者接受自体造血干细胞移植的一种新的预后标志物。
Natural killer (NK) cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governing NK cell function, therefore, may influence prognosis. Two highly polymorphic genetic loci instrumental in determining NK cell responses encode the NK cell killer immunoglobulin-like receptors (KIR) and their class I human leukocyte antigen (HLA) ligands. We hypothesized that patients with a “missing ligand” KIR-HLA compound genotype may uniquely benefit from autologous hematopoietic stem cell transplantation (HSCT). 169 patients treated with autologous HSCT for stage 4 neuroblastoma underwent KIR and HLA genotyping. Patients were segregated according to presence or absence of HLA ligands for autologous inhibitory KIR. Univariate and multivariate analyses were performed for overall and progression-free survival. 64% of patients lacked one or more HLA ligands for inhibitory KIR. Patients lacking an HLA ligand had a 46% lower risk of death (HR 0.54; 95% CI, 0.35–0.85, P=.007) and a 34% lower risk of progression (HR 0.66; 95% CI, 0.44–1.0; P=.047) at 3 years compared with patients who possessed all ligands for his/her inhibitory KIR. Among all KIR-HLA combinations, 16 patients lacking the HLA-C1 ligand for KIR2DL2/2DL3 experienced the highest 3-year survival rate of 81% (95% CI: 64–100). Survival was more strongly associated with “missing ligand” than with tumor MYCN gene amplification. KIR-HLA immunogenetics represents a novel prognostic marker for patients undergoing autologous HSCT for high-risk neuroblastoma.