Therapeutic targeting of metabolic interactions between cancer and immune cells to improve the graft-versus-leukemia effect

治疗靶向癌症和免疫细胞之间的代谢相互作用以改善移植物抗白血病效应

• 批准号: 492259164
• 负责人: Professorin Dr. Petya Apostolova
• 金额: --
• 依托单位: Departement Biomedizin
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/492259164?language=en
• 关键词: Therapeutic; targeting; metabolic; interactions; between

Acute myeloid leukemia (AML) is a malignant disease characterized by an uncontrolled proliferation of myeloblasts in the bone marrow leading to an aggressive clinical course in most patients. One potent curative treatment option for AML is allogeneic hematopoietic cell transplantation (allo-HCT), in which alloreactive T cells from a foreign donor eliminate residual leukemia cells. This process is termed graft-versus-leukemia effect (GVL). However, a significant percentage of allo-HCT recipients develop an AML relapse. AML relapse can be treated by administering donor lymphocyte infusions (DLI) in combination with cytotoxic drugs, but the success of this approach is limited. One possible mechanism that leads to immune evasion of AML cells is an altered metabolism resulting from selection pressure by the cytotoxic treatment and the donor immune system. Recognizing which metabolic pathways are employed by therapy-surviving AML cells could offer novel targets to strengthen the GVL effect.In preliminary experiments I observed that chemotherapy-resistant AML cells rewired their metabolism during recovery from cytotoxic stress. These cells accumulated several metabolites, including hexosamine biosynthesis pathway endpoint UDP-GlcNAc, which is essential for post-translational glycosylation of proteins, as well as the energy-rich metabolites creatine and phosphocreatine. Data from gene expression analysis and CRISPR-Cas9-induced deletion models suggested that increased abundance of creatine in the cells was due to elevated uptake from the microenvironment. Simultaneously, I found that T cells likewise accumulated creatine during effector function development and that deleting the creatine transporter SLC6A8 impaired T cell function by reducing cytokine production. In my project, I will focus on following aims: (i) to explore the impact of creatine metabolism in AML cells and T cells on the GVL effect; (ii) to test the potential of modulations in the hexosamine biosynthesis pathway and protein glycosylation for enhancement of the GVL effect; (iii) to determine the significance of oncogenic mutations and the type of AML treatment on metabolic competition between AML and T cells. I will achieve these objectives by using in vitro techniques and in vivo mouse models. The role of specific genes will be studied by CRISPR-Cas9-incuded knockdown and plasmid-mediated overexpression. Sample analysis will be performed by liquid-chromatography-mass spectrometry, RNA sequencing, flow cytometry and functional metabolic assays. The project will be supported by my host, Prof. Erika Pearce at the Johns Hopkins University School of Medicine, who will provide scientific expertise and the necessary technical equipment. This project aims to identify novel pharmacological strategies that target metabolic interactions between AML cells and T lymphocytes with the ultimate goal to boost the GVL effect and induce long-lasting AML remissions.

急性髓性白血病（AML）是一种恶性疾病，其特点是骨髓中成髓细胞增殖不受控制，导致大多数患者的临床病程具有侵袭性。同种异体造血细胞移植是治疗急性髓性白血病的一种有效的治疗选择，其中来自外源供体的同种异体反应性T细胞消除了残留的白血病细胞。这个过程被称为移植物抗白血病效应（GVL）。然而，很大比例的同种异体hct受体发生AML复发。AML复发可以通过供体淋巴细胞输注（DLI）联合细胞毒性药物治疗，但这种方法的成功是有限的。导致AML细胞免疫逃避的一种可能机制是细胞毒性治疗和供体免疫系统的选择压力导致的代谢改变。识别治疗存活的AML细胞所使用的代谢途径可以提供新的靶点来加强GVL的作用。在初步实验中，我观察到耐化疗的AML细胞在从细胞毒性应激中恢复的过程中重新连接了它们的代谢。这些细胞积累了几种代谢物，包括己糖胺生物合成途径终点UDP-GlcNAc，这是蛋白质翻译后糖基化所必需的，以及能量丰富的代谢物肌酸和磷酸肌酸。来自基因表达分析和crispr - cas9诱导缺失模型的数据表明，细胞中肌酸丰度的增加是由于微环境摄取增加所致。同时，我发现T细胞同样在效应功能发展过程中积累肌酸，删除肌酸转运体SLC6A8通过减少细胞因子的产生而损害T细胞功能。在我的项目中，我将重点关注以下目标：(I)探索AML细胞和T细胞中肌酸代谢对GVL效应的影响；（ii）测试调节己糖胺生物合成途径和蛋白质糖基化的潜力，以增强GVL的作用；（iii）确定致瘤突变和AML治疗类型对AML和T细胞之间代谢竞争的意义。我将通过使用体外技术和体内小鼠模型来实现这些目标。特定基因的作用将通过crispr - cas9包括敲低和质粒介导的过表达来研究。样品分析将通过液相色谱-质谱法、RNA测序、流式细胞术和功能代谢分析进行。我的东道主约翰霍普金斯大学医学院的Erika Pearce教授将支持这个项目，她将提供科学专门知识和必要的技术设备。该项目旨在确定针对AML细胞和T淋巴细胞之间代谢相互作用的新药理学策略，最终目标是增强GVL效应并诱导持久的AML缓解。