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Epigenetic regulation of T-cell dysfunction in chronic lymphocytic leukemia

慢性淋巴细胞白血病 T 细胞功能障碍的表观遗传调控

基本信息

批准号：
8856186
负责人：
HUIDONG SHI
金额：
$ 16.52万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856186
关键词：
Accounting Autologous Biological Biological Assay Biological Markers Blood CD4/CD8 ratio procedure CD8B1 gene Cancer Biology Cancer Immunology Science Cell physiology Cells Cessation of life Chemicals Chronic Lymphocytic Leukemia Clinical Clinical Trials Complication Control Groups DNA Methylation Disease Enzymes Epigenetic Process Failure Functional disorder Future Gene Expression Genes Goals Health Immune Immune System Diseases Immune response Immunosuppression Immunotherapy In Vitro Incidence Infection Laboratories Leukemic Cell Malignant Neoplasms Molecular Outcome Study Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase Phase I/II Trial Phenotype Play Positioning Attribute Predisposition Refractory Regulatory T-Lymphocyte Relapse Research Design Research Personnel Role Sampling Scientist Signal Transduction Signaling Molecule T-Cell Activation T-Lymphocyte Technology Tryptophan Tryptophan 2,3 Dioxygenase United States Up-Regulation adaptive immunity adult leukemia anergy base cancer immunotherapy chronic T-cell leukemia cost epigenetic marker epigenetic regulation epigenomics exhaustion immune function improved inhibitor/antagonist leukemia molecular marker multidisciplinary novel open label pressure repaired response tumor

项目摘要

DESCRIPTION (provided by applicant): One of the problems faced by CLL patients is that CLL leukemic cells induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. A critical barrier to progress in developing effective immunotherapy is the lack of understanding of molecular mechanisms responsible for the immune dysfunction in CLL. Alterations in levels of certain chemicals in the blood, such as the enzyme IDO, can induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. IDO inhibitors have entered the clinical arena with a promise to restore immune functions in CLL patients. Our central hypothesis is that CLL leukemic cells escape T cell dependent, adaptive immune responses by inducing immune suppressive pathways such as IDO signaling through epigenetic mechanisms. We further hypothesize that IDO blockage will repair the dysfunctional T cells in CLL patients. The objectives of our project are: 1) to determine epigenetic mechanisms of T cell dysfunction in CLL; and 2) to identify biomarkers that are associated with clinical response to an IDO inhibitor, 1-Methyl-D- tryptophan (1-MT), in samples collected from an investigator-initiated, open-label, phase I/II trial of 1-MT in relapsed/refractory CLL patients. We will identify gene expression and epigenetic signatures that are responsible for T cell dysfunction and determine if these biomarkers can predict the improved immune functions in CLL patients treated with 1-MT. The expected outcomes from this study are: 1) improved understanding of epigenetic mechanisms involved in activation of the IDO pathway in leukemia cells and autologous T cells from patients with CLL; and 2) identification of epigenetic biomarkers associated with T cell dysfunction in CLL patients as well as biomarkers that can predict the clinical response of 1-MT in clinical trials. The study will have significant impact on future clinical trials of 1-MT in caner patients. The results will also significantly improve our understanding of the underlying epigenetic mechanisms of tumor-driven immune dysfunction, and will aid the refinement of existing cancer immunotherapy strategies and identify novel targets. Because all cancers are associated with immune deficiency (anergy), and because the biological basis is poorly understood, the outcomes of this study are likely to have a significant broad-spectrum impact on cancer biology and immunology.

描述（申请人提供）：CLL患者面临的问题之一是CLL白血病细胞诱导免疫抑制状态，导致感染易感性增加和抗肿瘤免疫应答失败。发展有效免疫疗法的一个关键障碍是缺乏对CLL免疫功能障碍分子机制的理解。血液中某些化学物质（如IDO酶）水平的改变可诱导免疫抑制状态，导致感染易感性增加和抗肿瘤免疫应答失败。IDO抑制剂已进入临床竞技场，有望恢复CLL患者的免疫功能。我们的中心假设是CLL白血病细胞通过表观遗传机制诱导免疫抑制途径如IDO信号传导来逃避T细胞依赖性、适应性免疫应答。我们进一步假设IDO阻断将修复CLL患者中功能失调的T细胞。我们项目的目的是：1）确定CLL中T细胞功能障碍的表观遗传机制;和2）在从复发性/难治性CLL患者中的1-MT的促发剂启动的开放标签I/II期试验收集的样品中鉴定与对IDO抑制剂1-甲基-D-色氨酸（1-MT）的临床应答相关的生物标志物。我们将确定负责T细胞功能障碍的基因表达和表观遗传特征，并确定这些生物标志物是否可以预测1-MT治疗的CLL患者的免疫功能改善。本研究的预期结果是：1）提高了对参与CLL患者白血病细胞和自体T细胞中IDO途径活化的表观遗传机制的理解; 2）鉴定了与CLL患者T细胞功能障碍相关的表观遗传生物标志物以及可以预测临床试验中1-MT临床反应的生物标志物。该研究将对未来1-MT在癌症患者中的临床试验产生重大影响。这些结果还将显著提高我们对肿瘤驱动的免疫功能障碍的潜在表观遗传机制的理解，并将有助于完善现有的癌症免疫治疗策略和识别新的靶点。由于所有癌症都与免疫缺陷（无反应性）有关，并且由于生物学基础知之甚少，因此这项研究的结果可能对癌症生物学和免疫学产生重大的广谱影响。