Defective NK Cells in Acute Myeloid Leukemia Patients at Diagnosis Are Associated with Blast Transcriptional Signatures of Immune Evasion
Defective NK Cells in Acute Myeloid Leukemia Patients at Diagnosis Are Associated with Blast Transcriptional Signatures of Immune Evasion
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DOI：
10.4049/jimmunol.1500262
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发表时间：
2015-09-15
影响因子：
4.4
通讯作者：
Toubert, Antoine
中科院分区：
文献类型：
--
作者：
Khaznadar, Zena;Boissel, Nicolas;Toubert, Antoine
急性髓性白血病（AML）是一组异质性的恶性肿瘤，可能是敏感的NK细胞抗肿瘤反应。然而，NK细胞在AML中经常有缺陷。在这项研究中，我们在一个探索性队列（n = 46）中发现，AML诊断时的NK细胞状态将患者分为两组，具有不同的临床结局。NK细胞缺陷型患者，包括一些活化NK受体表达降低（例如，在多变量分析中，与细胞遗传学分类无关，DNAX辅助分子-1，NKp 46和NKG 2D）和IFN-γ产生减少具有显著更高的复发风险（p = 0.03）。NK细胞有缺陷的患者在AML母细胞中表现出细胞因子和趋化因子信号传导的基因表达显著降低（例如，IL 15、IFNGR 1、IFNGR 2和CXCR 4）、Ag加工（例如，HLA-DRB 1和CD 74）和粘附分子途径（例如，PVR和ICAM 1）。在探索性队列中定义的一组388个白血病分类器基因在194名AML患者的多中心队列中独立验证。总之，这些数据证明了诊断时NK细胞和AML原始细胞之间的相互作用，允许对AML患者进行独立于临床分类的基于免疫的分层。
Acute myeloid leukemia (AML) is a heterogeneous group of malignancies that may be sensitive to the NK cell antitumor response. However, NK cells are frequently defective in AML. In this study, we found in an exploratory cohort (n = 46) that NK cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK cell profile, including reduced expression of some activating NK receptors (e.g., DNAX accessory molecule-1, NKp46, and NKG2D) and decreased IFN-gamma production, had a significantly higher risk of relapse (p = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g., IL15, IFNGR1, IFNGR2, and CXCR4), Ag processing (e.g., HLA-DRA, HLA-DRB1, and CD74) and adhesion molecule pathways (e.g., PVR and ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications.