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

• 批准号: 10298027
• 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
• 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/10298027
• 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/antagonist; 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

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.

项目概要 T 细胞急性淋巴细胞白血病 (T-ALL) 是一种儿童和青少年侵袭性造血系统恶性肿瘤 经常出现治疗难治性和复发的成年人。尽管治愈率有所提高 强化多药化疗后，复发或难治性疾病仍很难治疗。 因此，对于识别新的脆弱性和治疗方法存在巨大的医学需求。 靶向免疫抑制肿瘤微环境已在许多实体瘤中取得了有希望的结果。 然而，对 T-ALL 微环境的全面研究对于表征 白血病/免疫细胞相互作用并确定治疗脆弱性尚未进行。使用单 T-ALL原始细胞及其微环境细胞的细胞测序技术，我们已经产生了初步的结果 数据表明免疫逃避在 T-ALL 中具有新作用，并有可能结合免疫治疗 克服 T 细胞衰竭的当前治疗方案。该提案旨在定义新颖的 T-ALL 的免疫逃逸机制并开发其治疗靶向的方法。我们将定义 通过结合 RNA-Seq、免疫组库和蛋白质分析来研究 CD8+ T 细胞功能障碍的机制 原发性 T-ALL 患者样本中的白血病和微环境细胞，并确定必要和 通过 T-ALL 体外和体内模型的功能扰动，使受体/配体充分耗尽（目标 1）；我们将研究调节 T-ALL 免疫逃避的表观遗传和转录机制，并开发 通过扰乱表观遗传机制来针对儿童白血病 T 细胞功能障碍的新策略（目标 2）。该提案的成功完成预计将揭示 T-免疫逃逸的新机制 ALL 并将导致针对 T 细胞衰竭的创新治疗策略的开发 高危 T-ALL 患者的免疫微环境。 T-ALL 中描述的原则将有一个 对多种恶性肿瘤有显着影响。