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

慢性淋巴细胞白血病(CLL)是成人中发病率最高的白血病。发病率随着年龄的增长而增加(确诊时的中位年龄为72岁)，导致德国每年约有3000名新确诊患者。临床治疗的范围从警惕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，很大比例的患者没有资格接受这种治疗。因此，改进现有的和/或开发新的基于免疫的方法(具有低系统毒性)为进一步扩大CLL的治疗选择提供了一条有希望的途径。CLL的特点是严重的免疫缺陷，导致感染并发症和抗肿瘤免疫反应不足。这些缺陷是由肿瘤微环境中恶性细胞和非恶性成分之间复杂的、双向的相互作用引起的。T细胞在数量、表型和功能上高度异常，同时仅具有有限的抗肿瘤免疫能力。事实上，当健康供者的T细胞与CLL细胞一起培养时，也可以观察到一些变化，从而突出了CLL细胞的免疫调节能力。最近的研究揭示了CLL来源的淋巴细胞的代谢缺陷：来自白血病宿主的T细胞在刺激时未能上调有氧糖酵解，而有氧糖酵解是启动T细胞有效激活的关键。此外，新陈代谢能力的恢复提高了CLL引导的T细胞免疫，突出了代谢和免疫功能是如何相互联系的。细胞串扰涉及包括外体在内的细胞外小泡。在生物发生过程中，外体装载了各种生物活性分子，包括细胞因子和RNA(如microRNA/miR)。CLL细胞结构性地释放外体，CLL细胞衍生的囊泡被结合到包括单核细胞和T细胞在内的免疫细胞中。CLL-exosome有一个明显的miR特征，我们最近发现通过CLL-exosome的miR转移干扰了髓系细胞的代谢，从而防止了有效的(治疗性)依赖抗体的CLL细胞杀伤。总而言之，新陈代谢决定了T细胞的功能，因此是控制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新陈代谢，从而促进免疫逃避。我们的初步数据表明，CLL-exosome调节T细胞生物学，包括新陈代谢。我们假设CLL-exosome在T细胞中产生新陈代谢，从而阻止有效的抗肿瘤免疫。我们的目的是为了更好地了解这种与CLL相关的免疫代谢干扰，以便识别预测CLL免疫缺陷的新生物标志物，从而使我们能够合理地设计代谢调节来提高抗CLL免疫。

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.