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: 10523526
• 负责人: Nicholas Chiorazzi
• 金额: $ 54.05万
• 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/10523526
• 关键词: Adoptive Immunotherapy; Affect; Aftercare; Autologous; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biology; Blood; CD4 Positive T Lymphocytes; Cancer Cell Growth; Cell Count; Cell Differentiation process; Cell Maturation; Cell Survival; Cell model; Cell secretion; Cells; Chronic Lymphocytic Leukemia; Clinical; Communication; Cues; Data; Development; Disease; Disease Progression; Elements; Engraftment; Experimental Models; FDA approved; Functional disorder; Future; Generations; Glean; Goals; Growth; Helper-Inducer T-Lymphocyte; IL17 gene; Immune; In Vitro; Individual; Knowledge; Laboratories; Learning; Link; Lymphoid Tissue; Mediating; Membrane; MicroRNAs; Modality; Molecular; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphorylation; Process; Proliferating; Publishing; 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; cell growth; chronic T-cell leukemia; chronic lymphocytic leukemia cell; cohort; curative treatments; cytokine; effective therapy; genetic approach; genome-wide analysis; immune modulating agents; improved; improved outcome; in vivo; inhibitor; innovation; leukemia; molecular modeling; receptor; 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.

项目概要/摘要 癌细胞的存活和生长取决于细胞接触和可溶性因子传递的环境线索。 这些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。这一原则在相对常见且仍无法治愈的慢性病中得到了例证。 淋巴细胞白血病 (CLL)，一种克隆性 CD5+ B 细胞疾病，需要来自膜的持续信号传导 肿瘤微环境中的受体和细胞。虽然已经收集到大量关于 关于 CLL B 细胞和自体 T 细胞之间的双向对话，目前关于这一点的信息很少 个体 T 细胞亚群，特别是 Th17 细胞，T 辅助细胞的独特亚群。科学前提是 该建议来自我们的研究结果，即在 CLL 中：[1] Th17 相关细胞因子水平较高，并且 循环 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 体外自体 CD4 T 细胞； [3] miR155 的表达显着促进 Th17 细胞分化 CLL 患者的 Th17 细胞含量高于健康受试者； [4] Th17 细胞调节 CLL B 细胞存活和 体外和体内生长； [5] 使用 PI3K 抑制剂治疗 CLL 患者的初始 CLL T 细胞 idelalisib 显着增强 Th17 细胞生成。这些发现奠定了我们的中心假设的基础，即 CLL B 细胞促进 Th17 细胞的产生，在白血病室内发挥抗肿瘤作用。 我们预计，增强 idelalisib 对 Th17 生成和功能产生积极影响的能力将显着 提高其临床价值。我们的长期目标是更清晰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。为了推进我们的 假设和目标，我们提出研究目的是： 阐明白血病的细胞和分子机制 B 细胞调节 CLL 中 Th17 细胞的生成，重点关注 STAT3/miR155 通路（目标 1）；确定 Th17 细胞对白血病 B 细胞体外和体内存活、生长和成熟的影响（目标 2）和 研究 idelalisib 对 CLL 中 Th17 细胞生成和功能的影响（目标 3）。拟议的工作是 创新性，因为它是第一个探索白血病 B 细胞调节生成的潜在机制 Th17 细胞的功能和功能以及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 的表达。此外，这些创新研究将产生相当大的影响 对 CLL 的影响，因为我们将确定 CLL 中生成 Th17 的机制以及该 T 细胞亚群的影响 对白血病 B 细胞生长、增殖和成熟的影响。最后，我们将确定 Th17 细胞数量是否较低 CLL 患者的预后不佳是由于 CLL T 或 B 细胞的固有差异造成的。这将有助于更好地 为未来关于如何增强 CLL 中 Th17 反应作为通过靶向治疗实现的治疗方式的研究提供信息 药物治疗或过继性免疫治疗。