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首页> 外文学位 >Down-regulation of signal transducer and activator of transcription 3 improves acute myeloid leukemia-derived dendritic cell function.
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Down-regulation of signal transducer and activator of transcription 3 improves acute myeloid leukemia-derived dendritic cell function.

机译：信号转导子和转录激活子3的下调改善了急性髓样白血病衍生的树突状细胞的功能。

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摘要

The only successful immunologic therapy in acute myeloid leukemia (AML) is allogeneic transplantation, however this approach has limitations. Therefore autologous therapies, including stimulating the patients' immune system with AML-derived dendritic cell (DC) vaccines, are being sought. Clinically these vaccines have proven to be less successful than anticipated. We have previously shown that constitutive signal transducer and activator of transcription (STAT) 3 activity is present in the blasts of approximately half of AML patients and correlates with poor prognosis. STAT3 regulates a variety of cellular events and has been shown to play a role in immuno-suppression by inhibiting DC differentiation, resulting in induction of T cell tolerance. Taken together, we hypothesize that AML-DC with constitutive STAT3 activity will have impaired ability to fully differentiate and efficiently stimulate T cells.;Methods. STAT3 inhibitory shRNAmirs and four JAK/STAT inhibitors (AG490, arsenic trioxide (ATO), JSI-124 and NSC-74859) were studied on AML-DCs from two cell lines, ten patient samples and three cord blood samples.;Results. AML blasts differentiated to DCs regardless of the level of activated STAT3, however AML-DC with high levels of activated STAT3 elicited less T cell response than AML-DC with low levels of activated STAT3. AML blasts transduced with STAT3 shRNAmir and differentiated to DCs formed functional AML-DC that increased stimulation of allogeneic T cells compared to control DCs in 4/4 patient samples without affecting immunophenotype or endocytotic activity. While the inhibitors were unable to enhance the early differentiation phase of DC development, when dosed during the last 24 hours of maturation, ATO led to enhanced T cell stimulation of in 2/2 AML cell lines and 8/9 patient samples compared to controls (p=0.0001), while having a minimal effect on cord blood-derived DC. ATO-treated AML-DCs had an increased number of cells expressing mature DC markers and supernatants from treated DCs contained higher amounts of the T cell stimulating cytokine IL-12p40.;These data demonstrate that AML-DCs have improved immunogenicity after reducing STAT3 protein levels during differentiation. Further, the observation that treatment with ATO is superior to the more targeted JAK/STAT inhibitors, suggests that DC maturation is not solely regulated by STAT3.
机译：急性髓细胞性白血病（AML）唯一成功的免疫疗法是同种异体移植，但是这种方法有局限性。因此，正在寻求自体疗法，包括用AML来源的树突状细胞（DC）疫苗刺激患者的免疫系统。临床上已证明这些疫苗未如预期的那样成功。先前我们已经表明，大约一半的AML患者的原始细胞中存在组成型信号转导子和转录激活子（STAT）3的活性，并且与不良预后相关。 STAT3调节多种细胞事件，并已显示出通过抑制DC分化而在免疫抑制中起作用，从而诱导T细胞耐受。两者合计，我们假设具有组成性STAT3活性的AML-DC将具有完全分化和有效刺激T细胞的能力受损。在来自两个细胞系，十个患者样品和三个脐带血样品的AML-DC上研究了STAT3抑制性shRNAmirs和四种JAK / STAT抑制剂（AG490，三氧化二砷（ATO），JSI-124和NSC-74859）。不管STAT3激活水平如何，AML母细胞都分化为DC，但是与STAT3激活水平较低的AML-DC相比，激活STAT3水平较高的AML-DC引起的T细胞应答更少。用STAT3 shRNAmir转导并分化成DC的AML母细胞形成功能性AML-DC，与4/4患者样品中的对照DC相比，它增加了同种T细胞的刺激，而不会影响免疫表型或内吞活性。虽然抑制剂无法增强DC发育的早期分化阶段，但在成熟的最后24小时内给药时，与对照组相比，ATO导致2/2 AML细胞系和8/9患者样品中的T细胞刺激增强（ p = 0.0001），而对脐带血DC的影响最小。 ATO处理的AML-DCs表达成熟DC标志物的细胞数量增加，处理过的DCs的上清液中T细胞刺激性细胞因子IL-12p40含量更高;这些数据表明AML-DCs在降低STAT3蛋白水平后具有更高的免疫原性。在分化过程中。此外，观察到用ATO治疗优于更具针对性的JAK / STAT抑制剂，这表明DC成熟不仅受STAT3调控。

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  • 作者

    Brady, Michael.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Biology Molecular.;Health Sciences Pathology.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 98 p.
  • 总页数 98
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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