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

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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.