Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents.
Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents.
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免疫检查点阻断正在成为一种新的抗癌治疗形式。我们研究了骨髓增生异常综合征（MDS）、慢性粒单核细胞白血病（CMML）和急性髓系白血病（AML）患者（N = 124）的CD34 +细胞中程序性死亡配体1（PD - L1）、程序性死亡配体2（PD - L2）、程序性死亡受体1（PD - 1）和细胞毒性T淋巴细胞相关蛋白4（CTLA4）信使核糖核酸（mRNA）的表达情况。在患者中分别观察到异常上调（≥2倍）的比例为34%、14%、15%和8%。在周围血单个核细胞（PBMNC，N = 61）中也观察到这4种基因表达增加。与AML相比，MDS（p = 0.018）和CMML（p = 0.0128）患者的PBMNC中PD - L1的相对表达显著更高。通过免疫组织化学（IHC）分析，在MDS的CD34 +细胞中观察到PD - L1蛋白表达，而基质/非原始细胞区室的PD - 1呈阳性。在一组接受表观遗传治疗的患者中，PD - L1、PD - L2、PD - 1和CTLA4的表达上调。与治疗有反应的患者相比，对治疗耐药的患者基因表达的相对增加幅度更高。用地西他滨治疗白血病细胞导致上述基因呈剂量依赖性上调。接触地西他滨导致白血病细胞系和人类样本中PD - 1部分去甲基化。这项研究表明PD - 1信号通路可能参与MDS的发病机制以及对去甲基化药物（HMAs）的耐药机制。阻断该通路可能是MDS和AML的一种潜在治疗方法。
Blockade of immune checkpoints is emerging as new form of anticancer therapy. We studied the expression of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in CD34+ cells from MDS, CMML and AML patients (N=124). Aberrant up-regulation (≥2 fold) was observed in 34%, 14%, 15% and 8% of the patients respectively. Increased expression of these 4 genes was also observed in PBMNC (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (p=0.018) and CMML (p=0.0128) compared to AML. By immunohistochemical (IHC) analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared to patients that achieved response. Treatment of leukemia cells with decitabine resulted in a dose dependent up-regulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to HMAs. Blockade of this pathway can be a potential therapy in MDS and AML.
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影响因子：
6.2
作者：
Jabbour, Elias;Garcia-Manero, Guillermo;Batty, Nicolas;Shan, Jenny;O'Brien, Susan;Cortes, Jorge;Ravandi, Farhad;Issa, Jean-Pierre;Kantarjian, Hagop
通讯作者：
Kantarjian, Hagop
影响因子：
11.5
作者：
Fonsatti, Ester;Nicolay, Hugues J. M.;Maio, Michele
通讯作者：
Maio, Michele
影响因子：
--
作者：
McDaniel JM;Pinilla-Ibarz J;Epling-Burnette PK
通讯作者：
Epling-Burnette PK
影响因子：
20.3
作者：
Soriano, Andres O.;Yang, Hui;Garcia-Manero, Guillermo
通讯作者：
Garcia-Manero, Guillermo
影响因子：
20.3
作者：
Greenberg, P;Cox, C;Bennett, J
通讯作者：
Bennett, J