Th17 generation, action and therapeutic relevance in chronic lymphocytic leukemia

项目总结/摘要 癌细胞的存活和生长取决于细胞接触和可溶性因子提供的环境线索。 这些因素决定了疾病的生物学和侵袭性，这反映在治疗方案的有效性上， 阻断营养输入。这一原则体现在相对常见的，仍然无法治愈的慢性 淋巴细胞性白血病（CLL），一种克隆性CD 5 + B细胞的疾病，需要从细胞膜持续的信号传导， 肿瘤微环境中的受体和细胞。虽然已经收集了大量关于 CLL B细胞和自体T细胞之间的双向对话，很少有关于 单个T细胞亚群，特别是Th 17细胞，T辅助细胞的独特亚群。科学的前提是 这一建议来自于我们的发现，即在CLL中：[1] Th 17相关细胞因子水平较高， 循环中的Th 17细胞与更好的临床结果相关; [2]白血病B细胞促进Th 17细胞的产生， [3]促进Th 17细胞分化的miR 155的表达显著增加， 来自CLL患者的Th 17细胞高于健康受试者; [4] Th 17细胞调节CLL B细胞存活， 体外和体内生长;和[5]用PI 3 K β抑制剂治疗来自CLL患者的幼稚CLL T细胞 Idelalisib显著增强Th 17细胞生成。这些发现支持了我们的中心假设，即慢性淋巴细胞白血病 B细胞促进Th 17细胞的产生，Th 17细胞在白血病区室中发挥抗肿瘤作用。 我们预期，增强艾代拉里斯布积极影响Th 17生成和功能的能力将显著地提高免疫应答。 提高其临床应用价值。我们的长期目标是更清楚地定义这种蜂窝双向通信 在分子水平上，以便操纵这些相互作用以获得治疗优势。把我们的 假设和目标，我们提出的研究：阐明细胞和分子机制，其中白血病 B细胞调节CLL中Th 17细胞的生成，重点是STAT 3/miR 155途径（Aim 1）; Th 17细胞在体外和体内对白血病B细胞存活、生长和成熟的影响（目的2）， 研究Idelalisib对CLL中Th 17细胞生成和功能的影响（目的3）。拟议的工作是 创新，因为它是第一个探索潜在的机制，白血病B细胞调节产生 和功能的Th 17细胞和这种调节对临床结果的影响;这也是第一个研究 CLL患者T细胞中全基因组miR表达。此外，这些创新的研究将有相当大的 对CLL的影响，因为我们将确定在CLL中产生Th 17的机制以及这种T细胞亚群对CLL的影响。 对白血病B细胞生长、增殖和成熟的影响。最后，我们将确定是否有较低的Th 17细胞数量， CLL患者预后差是由于CLL T或B细胞的固有差异。这将有助于更好地 为未来的研究提供信息，以了解如何增强CLL中的Th 17反应，作为靶向治疗方法 药物治疗或过继免疫治疗。

PROJECT SUMMARY/ABSTRACT Survival and growth of cancer cells depend on environmental cues delivered by cell contact and soluble factors. These shape disease biology and aggressiveness, reflected by the effectiveness of therapeutic regimens in blocking trophic inputs. This principle is exemplified in the relatively common and still incurable chronic lymphocytic leukemia (CLL), a disease of clonal CD5+ B cells requiring ongoing signaling from membrane receptors and cells within the tumor microenvironment. While considerable information has been gleaned about the bi-directional dialogue between CLL B cells and autologous T cells, little information is available about individual T-cell subsets, particularly Th17 cells, a unique subset of T helper cells. The scientific premise of this proposal comes from our findings that in CLL: [1] higher levels of Th17-related cytokines and numbers of circulating Th17 cells associate with better clinical outcomes; [2] leukemic B cells promote Th17 generation from autologous CD4 T cells in vitro; [3] expression of miR155, which promotes Th17 cell differentiation, is significantly higher in Th17 cells from CLL patients than in healthy subjects; [4] Th17 cells modulate CLL B-cell survival and growth in vitro and in vivo; and [5] treatment of naïve CLL T cells from CLL patients with the PI3K inhibitor idelalisib, significantly enhances Th17-cell generation. These findings underlie our central hypothesis that CLL B cells promote the generation of Th17 cells, which exert anti-tumor effects within the leukemic compartment. We expect that enhancing idelalisib's ability to positively affect Th17 generation and function will significantly improve its clinical value. Our long-range goal is to define this cellular bi-directional communication more clearly at the molecular level, so as to manipulate these interactions to therapeutic advantage. To advance our hypotheses and goal, we propose studies to: elucidate cellular and molecular mechanism(s) whereby leukemic B cells regulate Th17 cell generation in CLL, focusing on the STAT3/miR155 pathway (Aim 1); determine the influence of Th17 cells on leukemic B-cell survival, growth and maturation in vitro and in vivo (Aim 2) and investigate the effects of idelalisib on Th17-cell generation and function in CLL (Aim 3). The proposed work is innovative as it is the first to explore underlying mechanisms by which leukemic B cells regulate the generation and function of Th17 cells and the impact this regulation has on clinical outcome; it is also the first study of genome-wide miR expression in T cells from CLL patients. Also, these innovative studies will have considerable impact on CLL, since we will identify mechanisms generating Th17s in CLL and the impact this T-cell subset has on leukemic B cell growth, proliferation and maturation. Finally, we will determine if lower Th17-cell numbers in CLL patients with poor outcomes results from inherent differences in the CLL T or B cells. This will serve to better inform future studies on how to enhance Th17 responses in CLL as a therapeutic modality achieved by targeted drug therapy or adoptive immunotherapy.