Th17 generation, action and therapeutic relevance in chronic lymphocytic leukemia

慢性淋巴细胞白血病中 Th17 的产生、作用和治疗相关性

• 批准号: 9887955
• 负责人: Nicholas Chiorazzi
• 金额: $ 52.34万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887955
• 关键词: Adoptive Immunotherapy; Affect; Aftercare; Autologous; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Biochemical Genetics; Biology; Blood; CCL4 gene; CD4 Positive T Lymphocytes; Cell Count; Cell Differentiation process; Cell Maturation; Cell Survival; Cell model; Cells; Chronic Lymphocytic Leukemia; Clinical; Communication; Cues; Data; Development; Disease; Disease Progression; Elements; Experimental Models; FDA approved; Functional disorder; Future; Generations; Glean; Goals; Growth; Helper-Inducer T-Lymphocyte; Immune; Immunomodulators; In Vitro; Individual; Interleukin-17; Knowledge; Laboratories; Learning; Link; Lymphoid Tissue; Mediating; Membrane; MicroRNAs; Modality; Molecular; Molecular Analysis; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphorylation; Process; Publishing; Receptor Cell; Regimen; Regulation; Research; Role; STAT3 gene; Shapes; Signal Transduction; Stromal Cells; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Treatment Efficacy; Work; Xenograft procedure; adult leukemia; antitumor effect; base; cancer cell; cell growth; chronic T-cell leukemia; chronic lymphocytic leukemia cell; cohort; curative treatments; cytokine; effective therapy; genetic approach; genome-wide analysis; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; leukemia; molecular modeling; response; targeted treatment; therapeutic effectiveness; trafficking; translational study; tumor microenvironment

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.

项目摘要/摘要 癌细胞的生存和生长取决于细胞接触和固体因素提供的环境提示。 这些塑造疾病生物学和侵略性，反映出治疗方案在 阻止营养输入。该原理在相对常见且仍然无法治愈的慢性中举例说明 淋巴细胞白血病（CLL），一种克隆CD5+ B细胞的疾病，需要膜的信号传导 肿瘤微环境中的受体和细胞。虽然已经收集了大量信息 CLL B细胞与自体T细胞之间的双向对话，几乎没有有关的信息 单个T细胞子集，尤其是Th17细胞，是T辅助细胞的独特子集。科学前提 该提议来自我们的发现，即CLL：[1]与Th17相关的细胞因子和数量较高 循环Th​​17细胞与更好的临床结局相关； [2]白血病B细胞从 体外自体CD4 T细胞； [3]促进Th17细胞分化的miR155的表达显着 来自CLL患者的Th17细胞比健康受试者高； [4] Th17细胞调节CLL B细胞存活和 体外和体内生长； [5]从PI3K抑制剂的CLL患者中治疗幼稚的CLL T细胞 idelalisib，显着增强了Th17细胞的产生。这些发现是我们CLL的中心假设的基础 B细胞促进Th17细胞的产生，该细胞在白血病室内执行抗肿瘤作用。 我们希望增强idelalisib积极影响Th17的生成和功能的能力将大大显着 提高其临床价值。我们的远程目标是更清楚地定义这种蜂窝双向交流 在分子水平上，以操纵这些相互作用以获得治疗优势。促进我们的 假设和目标，我们提出研究以：阐明细胞和分子机制，在该机制中，白血病 B细胞调节CLL中Th17细胞的产生，重点是STAT3/MIR155途径（AIM 1）；确定 Th17细胞对白血病B细胞存活，体外和体内成熟的影响（AIM 2）和 研究idelalisib对CLL中Th17细胞生成和功能的影响（AIM 3）。拟议的工作是 创新性是第一个探索白血病B细胞来产生的潜在机制的基本机制 Th17细胞的功能以及该调节对临床结果的影响；这也是第一个研究 CLL患者的T细胞中全基因组miR的表达。另外，这些创新研究将考虑 对CLL的影响，因为我们将确定在CLL中产生Th17的机制以及该T细胞子集具有的影响 关于白血病B细胞生长，增殖和成熟。最后，我们将确定在 结局较差的CLL患者继承了CLL T或B细胞的差异。这将有助于更好 告知未来关于如何增强CLL中Th17响应作为目标的治疗方式的研究 药物治疗或适应性免疫疗法。