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异基因移植后复发AML细胞的免疫逃逸
Immune Escape of Relapsed AML Cells after Allogeneic Transplantation


Matthew J. Christopher ... 肿瘤 • 2018.12.13
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摘要


背景

作为急性髓系白血病(AML)的巩固治疗,异基因造血干细胞移植的获益有部分是通过免疫介导的移植物抗白血病作用产生。我们假设,异基因移植产生的免疫介导的选择压力可能导致复发性疾病中不同的肿瘤演化模式。

 

方法

本研究纳入了造血干细胞移植(移植物来自HLA相合的同胞、HLA相合的无关供者或HLA不合的无关供者)后复发的15例患者和化疗后复发的20例患者,对其因AML初次就诊时和复发时的配对样本进行了增强外显子组测序。我们对这些样本的一个亚组和其他样本进行了RNA测序和流式细胞术检测,用于验证之目的。

 

结果

在外显子组测序中,移植后复发时观察到的获得和丢失突变谱与化疗后复发时观察到的突变谱相似。具体而言,移植后复发时,免疫相关基因未获得先前未知的AML特异性突变或结构变异。相比之下,移植后复发时所采集样本的RNA测序显示,涉及适应性和先天免疫的途径失调,包括主要组织相容性复合体(MHC)Ⅱ类基因(HLA-DPA1HLA-DPB1HLA-DQB1HLA-DRB1)水平下调至初次就诊时所采集的配对样本的1/12~1/3。流式细胞术和免疫组化分析证实,在移植后复发的34例患者中,17例在复发时有MHC Ⅱ类基因表达下降。有证据提示,γ干扰素可以在体外快速逆转AML母细胞的这一表型。

 

结论

移植后AML复发时,免疫相关基因未获得复发特异性突变。然而,可能影响免疫功能的途径发生失调,包括参与抗原呈递的MHC Ⅱ类基因下调。通过适当治疗,这些表观遗传变化可能是可逆的(由美国国立癌症研究所[National Cancer Institute]等资助)。





作者信息

Matthew J. Christopher, M.D., Ph.D., Allegra A. Petti, Ph.D., Michael P. Rettig, Ph.D., Christopher A. Miller, Ph.D., Ezhilarasi Chendamarai, Ph.D., Eric J. Duncavage, M.D., Jeffery M. Klco, M.D., Ph.D., Nicole M. Helton, B.S., Michelle O’Laughlin, B.S., Catrina C. Fronick, B.S., Robert S. Fulton, M.S., Richard K. Wilson, Ph.D., Lukas D. Wartman, M.D., John S. Welch, M.D., Ph.D., Sharon E. Heath, Jack D. Baty, B.A., Jacqueline E. Payton, M.D., Ph.D., Timothy A. Graubert, M.D., Daniel C. Link, M.D., Matthew J. Walter, M.D., Peter Westervelt, M.D., Ph.D., Timothy J. Ley, M.D., and John F. DiPersio, M.D., Ph.D.
From the Division of Oncology, Department of Internal Medicine (M.J.C., A.A.P., M.P.R., C.A.M., E.C., N.M.H., L.D.W., J.S.W., S.E.H., D.C.L., M.J.W., P.W., T.J.L., J.F.D.), the McDonnell Genome Institute (A.A.P., C.A.M., M.O., C.C.F., R.S.F., L.D.W., T.J.L.), the Department of Pathology and Immunology (E.J.D., J.E.P.), and the Division of Biostatistics (J.D.B.), Washington University in St. Louis, St. Louis; the Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN (J.M.K.); the Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH (R.K.W.); and the Center for Cancer Research, Massachusetts General Hospital, Boston (T.A.G.). Address reprint requests to Dr. Ley at the Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Box 8007, St. Louis, MO 63110, or at timley@wustl.edu.

 

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