Elucidating the role of the CXCL13/CXCR5 signaling axis in Angioimmunoblastic T-Cell Lymphoma (AITL)

阐明 CXCL13/CXCR5 信号轴在血管免疫母细胞 T 细胞淋巴瘤 (AITL) 中的作用

• 批准号: 9394539
• 负责人: Eric M Rosenberg
• 金额: $ 2.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394539
• 关键词: Affect; Agonist; Alleles; Antibody Affinity; Autoimmune Diseases; B-Cell Activation; B-Lymphocytes; BLR1 gene; Basic Science; Binding; Binding Proteins; Biological Assay; Biological Response Modifier Therapy; Blood; Breeding; CD4 Positive T Lymphocytes; CRISPR/Cas technology; CXCL13 gene; Cell Line; Cell Maturation; Cell Proliferation; Cell Survival; Cells; Characteristics; Chemotaxis; Chimeric Proteins; Clinic; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Dose; Drug Kinetics; Exhibits; Family; Feedback; Follicular Dendritic Cells; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Generations; Genes; Genetic; Genotype; Helper-Inducer T-Lymphocyte; Heterozygote; Histologic; Human; Immune system; Immunoblastic Lymphadenopathy; Immunoglobulin Somatic Hypermutation; Individual; Interferon Type II; Interleukin-2; Interleukin-6; Knock-out; Ligands; Literature; Lymphoid; Malignant Neoplasms; Mammalian Cell; Mediator of activation protein; Medical; Messenger RNA; Methods; Modification; Molecular; Monitor; Mus; Mutation; N-terminal; Non-Hodgkin' s Lymphoma; Organ; Pathogenesis; Patients; Peripheral; Phagocytosis; Phenotype; Physiological; Play; Point Mutation; Process; Production; Proteins; Recruitment Activity; Regimen; Research; Role; Schedule; Severities; Signal Transduction; Signaling Molecule; Structure of germinal center of lymph node; Subcutaneous Injections; Suggestion; Survival Rate; System; T-Cell Lymphoma; T-Lymphocyte; Techniques; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor Necrosis Factor-Beta; adaptive immunity; antibody-dependent cell cytotoxicity; autocrine; chemokine; diagnostic biomarker; genetic signature; genome editing; in vivo; large scale production; member; mouse model; mutant; neoplastic; neoplastic cell; novel; outcome forecast; overexpression; promoter; receptor; stable cell line; targeted cancer therapy; targeted treatment; therapeutic target; tumor

Project Summary/Abstract Angioimmunoblastic T-Cell Lymphoma (AITL) is a rare type of non-Hodgkin lymphoma (NHL). To date, there are no targeted therapies for the cancer, which is reflected in a dismal five-year overall survival rate at around 30% following conventional chemotherapeutic regimens. Clinicopathological analysis of affected individuals has revealed that a member of the chemokine family—CXCL13—is consistently upregulated in neoplastic tissues, and it is now used as a diagnostic marker for the disease. The cognate receptor for CXCL13, CXCR5, is a G protein-coupled receptor (GPCR) that is expressed on B lymphocytes as well as a small subset of CD4+ T lymphocytes known as Follicular Helper T cells (TFH). TFH cells are believed to be the neoplastic cell of origin in AITL, as the gene signature of AITL has been shown to be enriched in genes that are markers for these cells, including CXCL13. This chemokine is necessary for B cell recruitment into germinal centers and for B cell activation in a normal physiological setting. In AITL, there is indication that aberrant expression of CXCL13 may activate an autocrine feedback loop by binding to CXCR5 on TFH cells, possibly contributing to their proliferation and survival; CXCL13 is also thought to cause B cell activation in the cancer, leading to their secretion of effector molecules that cause Follicular Dendritic Cell (FDC) proliferation and invasion into the tumorous tissues. FDCs are then thought to intimately associate with T cells in the tumor, promoting the TFH phenotype. These autocrine and positive feedback loops could be blocked by antagonism of the CXCL13/CXCR5 signaling axis. Our lab believes that blockade of CXCR5 may serve as an effective targeted therapeutic for patients with AITL. A mouse model of AITL is available for use in basic research—these mice exhibit a point mutation in an mRNA-binding protein known as Roquin. Heterozygosity for this so-called “sanroque” mutation (i.e., Roquinsan/+ genotype) causes mice to develop tumors that display histologic features diagnostic of AITL. We propose to discern CXCR5's role in disease pathogenesis and use as a therapeutic target for the disease. The two aims of this proposal are: 1. Develop a CXCR5 antagonist biotherapeutic for in vivo studies in Roquinsan/+ mice via N- terminal modification of CXCL13, a common technique to convert chemokines from agonists into antagonists; 2. Generate and characterize a CD4 promoter-driven inducible CXCR5 knockout in the Roquinsan/+ background. These studies will provide a formal understanding of the role that the CXCL13/CXCR5 axis plays in AITL, and may serve as a proof-of-principle for development of a biotherapeutic targeting CXCR5 in humans for use in the clinic.

项目总结/摘要 血管免疫母细胞性T细胞淋巴瘤（AITL）是一种罕见的非霍奇金淋巴瘤（NHL）。到目前为止， 目前还没有针对这种癌症的靶向治疗方法，这反映在令人沮丧的五年总生存率上， 在常规化疗方案后约为30%。20例肺癌临床病理分析 研究人员发现，趋化因子家族的一个成员-CXCL13-在人的免疫系统中持续上调， 肿瘤组织中，它现在被用作疾病的诊断标志物。的同源受体 CXCL 13，CXCR 5，是一种G蛋白偶联受体（GPCR），在B淋巴细胞上表达， 小的CD4 + T淋巴细胞亚群，称为滤泡辅助T细胞（TFH）。TFH细胞被认为是 AITL中的肿瘤细胞起源，因为AITL的基因标记已显示富集于 是这些细胞的标志物，包括CXCL13。这种趋化因子是B细胞募集到 在正常生理环境中，用于生发中心和B细胞活化。在AITL，有迹象表明， CXCL 13的异常表达可通过结合TFH细胞上的CXCR 5激活自分泌反馈环， 可能有助于它们的增殖和存活; CXCL 13也被认为在淋巴细胞中引起B细胞活化。 癌症，导致它们分泌引起滤泡树突状细胞（FDC）增殖的效应分子 并侵入肿瘤组织。然后认为FDC与肿瘤中的T细胞密切相关， 促进TFH表型。这些自分泌和正反馈循环可以被拮抗剂阻断， CXCL13/CXCR5信号轴。我们的实验室认为，阻断CXCR5可能是一种有效的 AITL患者的靶向治疗。 AITL的小鼠模型可用于基础研究-这些小鼠在一个基因组中表现出点突变， 一种叫做Roquin的mRNA结合蛋白这种所谓的“Sanroque”突变的杂合性（即，Roquinsan/+ 基因型）导致小鼠产生显示诊断AITL的组织学特征的肿瘤。我们建议 识别CXCR5在疾病发病机制中的作用，并用作疾病的治疗靶点。的两个目标 这些建议是：1.开发CXCR5拮抗剂biflavin，用于Roquinsan/+小鼠体内研究，通过N- CXCL 13的末端修饰，一种将趋化因子从激动剂转化为拮抗剂的常用技术; 2.在Roquinsan/+背景下生成并表征CD4启动子驱动的诱导型CXCR5敲除。 这些研究将提供对CXCL 13/CXCR 5轴在AITL中所起作用的正式理解， 可以作为开发靶向人类CXCR 5的生物治疗剂的原理验证，用于 诊所