Mechanisms of immune evasion in T-cell acute lymphoblastic leukemia and its therapeutic implications

T细胞急性淋巴细胞白血病的免疫逃避机制及其治疗意义

基本信息

批准号：
10474616
负责人：
Birgit Knoechel
金额：
$ 40.57万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474616
关键词：
3-Dimensional Acute T Cell Leukemia Address Blood CD19 gene CD8-Positive T-Lymphocytes CRISPR screen CRISPR/Cas technology Cell Communication Cells Child Childhood Leukemia Chromatin Chromosomes Clinical Data Development EP300 gene Enhancers Epigenetic Process Functional disorder Galactose Binding Lectin Generations Genetic Genetic Engineering Genetic Transcription Hematopoietic Neoplasms Human Immune Immune Evasion Immune Targeting Immunotherapeutic agent Immunotherapy In Vitro Kinetics Large-Scale Sequencing Ligand Binding Ligands Malignant Neoplasms Malignant lymphoid neoplasm Manuscripts Maps Medical Menin Molecular Molecular Conformation Myeloproliferative disease Oncogenic Pathway interactions Patients Prognosis Protein Analysis Refractory Refractory Disease Relapse Research Role Sampling Solid Neoplasm Subgroup T cell response T cell therapy T-Lymphocyte Technology Testing Therapeutic Treatment Protocols base chemotherapy exhaust exhaustion experimental study genome editing genome-wide high risk improved in vivo Model inhibitor innovation leukemia mouse model new therapeutic target novel novel strategies novel therapeutic intervention receptor resistance mechanism response single cell sequencing success targeted treatment therapeutic target transcription factor transcriptome sequencing treatment strategy tumor-immune system interactions young adult

项目摘要

Project Summary T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy in children and young adults that frequently becomes treatment-refractory and relapses. Although cure rates have improved with intensified multi-agent chemotherapy, relapsed or treatment refractory disease remains very difficult to treat. Therefore, there is a great medical need for identifying novel vulnerabilities and therapeutic approaches. Targeting of the immunosuppressive tumor microenvironment has led to promising results in many solid tumors. Yet, comprehensive studies of the T-ALL microenvironment, which are necessary to characterize leukemia/immune cell interactions and identify therapeutic vulnerabilities, have not been performed. Using single cell sequencing technologies of T-ALL blasts and their microenvironmental cells, we have generated preliminary data suggesting a novel role of immune evasion in T-ALL with the potential to incorporate immunotherapy approaches into current treatment regimens to overcome T-cell exhaustion. This proposal seeks to define novel mechanisms of immune evasion in T-ALL and develop means for their therapeutic targeting. We will define mechanisms of CD8+ T-cell dysfunction by combining RNA-Seq, immune repertoire and protein analysis in single leukemia and microenvironmental cells in primary T-ALL patient samples and determine the necessary and sufficient exhaustion receptor/ligands through functional perturbation in in vitro and in vivo models of T-ALL (aim 1); We will study epigenetic and transcriptional mechanisms that regulate immune evasion in T-ALL and develop novel strategies to target T-cell dysfunction in pediatric leukemias by perturbing the epigenetic machinery (aim 2). Successful completion of this proposal is expected to uncover novel mechanisms of immune evasion in T- ALL and will lead to development of innovative therapeutic strategies for targeting T-cell exhaustion in the immune microenvironment in patients with high-risk T-ALL. The principles described in T-ALL will have a significant impact on a wide variety of malignancies.

项目摘要 T细胞急性淋巴细胞白血病（T-ALL）是儿童和年轻人的侵略性造血恶性肿瘤经常变成治疗症状并复发的成年人。尽管治愈率有所提高加强的多药化疗，复发或治疗难治性疾病仍然很难治疗。因此，有很大的医疗需求来识别新颖的脆弱性和治疗方法。靶向免疫抑制肿瘤微环境已导致许多实体瘤的结果。然而，对T-ALL微环境的全面研究是表征的必要条件尚未进行白血病/免疫细胞相互作用并识别治疗脆弱性。使用单个 T-ALL爆炸及其微环境细胞的细胞测序技术，我们已经产生了初步数据表明免疫逃避在T-All中具有新颖的作用，并具有纳入免疫疗法的潜力进入当前治疗方案以克服T细胞疲劳。该提议旨在定义小说 T-ALL中免疫逃避的机制，并为其治疗靶向开发手段。我们将定义通过将RNA-seq，免疫库和蛋白质分析组合在单一的CD8+ T细胞功能障碍的机制主要T-ALL患者样品中的白血病和微环境细胞，并确定必要的和通过在体外和体内T-all的体外和体内通过功能扰动，足够的疲惫受体/配体（AIM 1）;我们将研究调节T-All的免疫逃避并发展的表观遗传和转录机制通过扰动表观遗传机制来靶向小儿白血病中T细胞功能障碍的新型策略（AIM 2）。预计该提案的成功完成将发现T-中免疫逃避的新机制一切，并将导致针对T细胞疲惫的创新治疗策略的发展高危T-ALL患者的免疫微环境。 T-All中描述的原则将有一个对各种恶性肿瘤的重大影响。