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

项目摘要 T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性的造血系统恶性肿瘤，好发于儿童和青少年 成年人，经常成为治疗难治性和复发。虽然治愈率有所提高， 强化多药化疗后，复发或难治性疾病仍然很难治疗。 因此，有一个伟大的医学需要确定新的弱点和治疗方法。 靶向免疫抑制性肿瘤微环境已经在许多实体瘤中产生了有希望的结果。 然而，对T-ALL微环境的全面研究， 白血病/免疫细胞相互作用和鉴定治疗弱点的研究尚未进行。使用单 T-ALL母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 数据表明免疫逃避在T-ALL中的新作用，有可能纳入免疫治疗 目前的治疗方案，以克服T细胞耗竭的方法。该提案旨在定义小说 研究T-ALL中的免疫逃避机制，并开发其治疗靶向的方法。我们将定义 CD 8 + T细胞功能障碍的机制，通过结合RNA-Seq，免疫库和蛋白质分析， 白血病和微环境细胞在原发性T-ALL患者样本，并确定必要的， 在T-ALL的体外和体内模型中通过功能扰动充分耗尽受体/配体（目的 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 通过干扰表观遗传机制靶向儿童白血病T细胞功能障碍的新策略（目的 2）。该提案的成功完成有望揭示T细胞免疫逃避的新机制， ALL，并将导致针对T细胞耗竭的创新治疗策略的发展， 高危T-ALL患者的免疫微环境。T-ALL中描述的原理将具有 对多种恶性肿瘤有显著影响。

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.