The immunometabolic reprogramming of human T-cells by chronic lymphocytic leukemia-derived exosomes

慢性淋巴细胞白血病衍生的外泌体对人类 T 细胞的免疫代谢重编程

• 批准号: 404074532
• 负责人: Professor Dr. Dimitrios Mougiakakos
• 金额: --
• 依托单位: Klinik für Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404074532?language=en
• 关键词: immunometabolic; reprogramming; human; cells; chronic

Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence amongst adults. Incidence increases with age (=median age at diagnosis is 72 years) leading to ca. 3000 newly diagnosed patients/year in Germany. Clinical management ranges from watchful waiting to chemo-immunotherapy. However, cure can only be achieved by allogeneic stem cell transplantation, which is associated with high rates of mortality. A high proportion of patients would not be eligible for such treatment due to advanced age and comorbidities. Therefore, improving existing and/or developing novel immune-based approaches (of low systemic toxicity) pose a promising path for further expanding treatment options in CLL. CLL is characterized by profound immune defects, leading to infectious complications and inadequate antitumor immune responses. These deficiencies are caused by complex, bi-directional interactions between malignant cells and nonmalignant components of the tumor microenvironment. T-cells are numerically, phenotypically, and functionally highly abnormal, while holding only limited abilities to exert antitumor immunity. In fact, several of the alterations can also be observed in healthy donor-derived T-cells when cultured in presence of CLL-cells thus highlighting the immunomodulatory capacity of CLL-cells. Recent studies revealed metabolic defects in CLL-derived lymphocytes: T-cells from leukemic hosts failed to up-regulate aerobic glycolysis upon stimulation, which is critical for mounting an efficient T-cell activation. Moreover, restoring metabolic competence improved CLL-directed T-cell immunity highlighting how metabolic and immunologic functionality is interconnected. Cellular crosstalk involves extracellular vesicles including exosomes. During biogenesis exosomes are loaded with various biologically active molecules including cytokines and RNA (such as microRNA/miR). CLL-cells constitutively release exosomes and CLL-cell-derived vesicles are incorporated into immune cells including monocytes and T-cells. CLL-exosomes have a distinct miR signature and we have recently shown that miR transfer via CLL-exosomes interferes with myeloid cell metabolism thereby preventing amongst others an efficient (therapeutic) antibody dependent CLL-cell killing. Taken together, metabolism determines what a T-cell does and thereby represents an ideal tool for controlling T-cell function. However, increasing evidence suggest that malignant cells interfere with immune cell metabolism thereby promoting immune evasion. Our preliminary data suggest that CLL-exosomes modulate T-cell biology including metabolism. We hypothesize that CLL-exosomes confer metabolic hits in T-cells thereby preventing efficient anti-tumor immunity. Our aim is to better understand this CLL-associated immunometabolic interference in order to identify novel biomarkers predicting immune deficiencies in CLL allowing us a rational design of metabolic modulation for improving anti-CLL immunity.

慢性淋巴细胞白血病（CLL）是成人中发病率最高的白血病。发病率随年龄增加（=诊断时的中位年龄为72岁），导致ca。德国每年新诊断患者3000例。临床管理范围从观察等待到化学免疫治疗。然而，治愈只能通过异基因干细胞移植来实现，这与高死亡率有关。由于高龄和合并症，很大比例的患者不适合接受此类治疗。因此，改善现有的和/或开发新的基于免疫的方法（低全身毒性）为进一步扩大CLL的治疗选择提供了一条有希望的途径。CLL的特征在于严重的免疫缺陷，导致感染性并发症和抗肿瘤免疫应答不足。这些缺陷是由肿瘤微环境的恶性细胞和非恶性成分之间复杂的双向相互作用引起的。T细胞在数量、表型和功能上高度异常，同时仅具有有限的发挥抗肿瘤免疫的能力。事实上，当在CLL细胞存在下培养时，也可以在健康供体来源的T细胞中观察到几种改变，从而突出CLL细胞的免疫调节能力。最近的研究揭示了CLL衍生的淋巴细胞中的代谢缺陷：来自白血病宿主的T细胞在刺激时未能上调有氧糖酵解，这对于建立有效的T细胞活化至关重要。此外，恢复代谢能力改善了CLL导向的T细胞免疫，突出了代谢和免疫功能是如何相互联系的。细胞串扰涉及细胞外囊泡，包括外来体。在生物发生期间，外来体装载有各种生物活性分子，包括细胞因子和RNA（如microRNA/miR）。CLL细胞组成性地释放外泌体，并且CLL细胞衍生的囊泡被并入包括单核细胞和T细胞的免疫细胞中。CLL-外泌体具有独特的miR特征，并且我们最近已经表明，通过CLL-外泌体的miR转移干扰骨髓细胞代谢，从而防止有效的（治疗性）抗体依赖性CLL-细胞杀伤等。总之，代谢决定了T细胞的功能，因此代表了控制T细胞功能的理想工具。然而，越来越多的证据表明，恶性细胞干扰免疫细胞代谢，从而促进免疫逃避。我们的初步数据表明，CLL-外泌体调节T细胞生物学，包括代谢。我们假设CLL-外泌体在T细胞中赋予代谢命中，从而阻止有效的抗肿瘤免疫。我们的目的是更好地了解这种CLL相关的免疫代谢干扰，以确定预测CLL免疫缺陷的新生物标志物，从而使我们能够合理设计代谢调节以改善抗CLL免疫力。