Th17 generation, action and therapeutic relevance in chronic lymphocytic leukemia

项目摘要/摘要 癌细胞的存活和生长依赖于细胞接触和可溶性因子传递的环境信号。 这些因素塑造了疾病生物学和侵袭性，反映在治疗方案的有效性上 阻断营养输入。这一原则在相对常见且仍无法治愈的慢性疾病中得到了体现。 淋巴细胞性白血病(CLL)，一种克隆性CD5 B细胞疾病，需要膜上持续的信号 肿瘤微环境中的受体和细胞。虽然已经收集了大量的信息 CLL B细胞和自体T细胞之间的双向对话，关于这方面的信息很少 单个T细胞亚群，特别是Th17细胞，这是T辅助细胞的一个独特的子集。科学的前提是 这一建议来自我们的发现，在CLL：[1]更高水平的Th17相关细胞因子和数量 循环中的Th17细胞与更好的临床结果相关；[2]白血病B细胞促进Th17的产生 [3]促进Th17细胞分化的miR155的表达显著增加 慢性淋巴细胞性白血病患者Th17细胞高于健康人；[4]Th17细胞调节CLL B细胞存活和 体外和体内生长；PI3K抑制剂治疗慢性淋巴细胞性白血病患者的幼稚CLL T细胞 Idelalisib可显著增强Th17细胞的生成。这些发现支持了我们的中心假设，即CLL B细胞促进Th17细胞的产生，Th17细胞在白血病间隔内发挥抗肿瘤作用。 我们预计，增强idelalisib对Th17产生和功能的积极影响的能力将显著 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，从而操纵这些相互作用以获得治疗优势。为了推进我们的 假设和目标，我们提出研究：阐明白血病的细胞和分子机制(S) B细胞调节CLL中Th17细胞的生成，集中在STAT3/miR155途径(目标1)；确定 Th17细胞对白血病B细胞体内外存活、生长和成熟的影响(AIM 2)和 研究idelalisib对慢性淋巴细胞性白血病Th17细胞生成和功能的影响(目标3)。建议的工作是 具有创新性，因为它是第一次探索白血病B细胞调节生成的潜在机制 和Th17细胞的功能以及这种调节对临床结局的影响；这也是第一个关于 慢性淋巴细胞性白血病患者T细胞中miR的全基因组表达此外，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中生成Th17的机制以及这个T细胞亚群具有的影响 对白血病B细胞生长、增殖和成熟的影响。最后，我们将确定是否在 CLL患者预后较差是由于CLL T或B细胞的固有差异所致。这将有助于更好地 告知未来研究如何在CLL中增强Th17应答，作为靶向治疗方式 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.