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

项目摘要 T细胞急性淋巴细胞性白血病(T-ALL)是一种儿童和年轻人的侵袭性血液系统恶性肿瘤 经常成为治疗难治和复发的成年人。尽管治愈率随着 加强多药联合化疗，复发或治疗难治性疾病仍很难治疗。 因此，医学上非常需要识别新的脆弱性和治疗方法。 靶向免疫抑制的肿瘤微环境已经在许多实体肿瘤中取得了令人满意的结果。 然而，对T-ALL微环境的全面研究，是表征 在白血病/免疫细胞相互作用和确定治疗脆弱性方面，尚未进行研究。使用Single T-ALL细胞及其微环境细胞的细胞测序技术 数据显示免疫逃避在T-ALL中的新作用，并有可能纳入免疫治疗 探讨目前克服T细胞衰竭的治疗方案。这项提议试图定义小说 T-ALL的免疫逃逸机制及其治疗靶向的发展。我们将定义 联合RNA-Seq、免疫谱系和蛋白质分析研究CD8T细胞功能障碍的机制 白血病和微环境细胞在原发T-ALL患者样本中的变化并确定必要和 在T-ALL体外和体内模型中通过功能扰动获得足够的力竭受体/配体(AIM 1)；我们将研究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(AIM 2)。这一提议的成功完成有望揭示T细胞免疫逃避的新机制。 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患者免疫微环境的研究T-ALL中描述的原则将具有 对多种恶性肿瘤有重大影响。

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.