Background: Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of malignant B-cells and multiple immune defects. This leads, among others, to severe infectious complications and inefficient immune surveillance. T-cell deficiencies in CLL include enhanced immune(-metabolic) exhaustion, impaired activation and cytokine production, and immunological synapse malformation. Several studies have meanwhile reported CLL-cell–T-cell interactions that culminate in T-cell dysfunction. However, the complex entirety of their interplay is incompletely understood. Here, we focused on the impact of CLL cell-derived vesicles (EVs), which are known to exert immunoregulatory effects, on T-cell function. Methods: We characterized EVs secreted by CLL-cells and determined their influence on T-cells in terms of survival, activation, (metabolic) fitness, and function. Results: We found that CLL-EVs hamper T-cell viability, proliferation, activation, and metabolism while fostering their exhaustion and formation of regulatory T-cell subsets. A detailed analysis of the CLL-EV cargo revealed an abundance of immunological checkpoints (ICs) that could explain the detected T-cell dysregulations. Conclusions: The identification of a variety of ICs loaded on CLL-EVs may account for T-cell defects in CLL patients and could represent a barrier for immunotherapies such as IC blockade or adoptive T-cell transfer. Our findings could pave way for improving antitumor immunity by simultaneously targeting EV formation or multiple ICs.

One of the key challenges for successful cancer therapy is the capacity of tumors to evade immune surveillance. Tumor immune evasion can be accomplished through the induction of T cell exhaustion via the activation of various immune checkpoint molecules. The most prominent examples of immune checkpoints are PD-1 and CTLA-4. Meanwhile, several other immune checkpoint molecules have since been identified. One of these is the T cell immunoglobulin and ITIM domain (TIGIT), which was first described in 2009. Interestingly, many studies have established a synergistic reciprocity between TIGIT and PD-1. TIGIT has also been described to interfere with the energy metabolism of T cells and thereby affect adaptive anti-tumor immunity. In this context, recent studies have reported a link between TIGIT and the hypoxia-inducible factor 1-α (HIF1-α), a master transcription factor sensing hypoxia in several tissues including tumors that among others regulates the expression of metabolically relevant genes. Furthermore, distinct cancer types were shown to inhibit glucose uptake and effector function by inducing TIGIT expression in CD8+ T cells, resulting in an impaired anti-tumor immunity. In addition, TIGIT was associated with adenosine receptor signaling in T cells and the kynurenine pathway in tumor cells, both altering the tumor microenvironment and T cell-mediated immunity against tumors. Here, we review the most recent literature on the reciprocal interaction of TIGIT and T cell metabolism and specifically how TIGIT affects anti-tumor immunity. We believe understanding this interaction may pave the way for improved immunotherapy to treat cancer.

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Summary IL‐33 is a member of the IL‐1 family. By binding to its receptor ST2 (IL‐33R) on mast cells, IL‐33 induces the MyD88‐dependent activation of the TAK1‐IKK2 signalling module resulting in activation of the MAP kinases p38, JNK1/2 and ERK1/2, and of NFκB. Depending on the kinases activated in these pathways, the IL‐33‐induced signalling is essential for production of IL‐6 or IL‐2. This was shown to control the dichotomy between RORγt+ and Helios+ Tregs, respectively. SCF, the ligand of c‐Kit (CD117), can enhance these effects. Here, we show that IL‐3, another growth factor for mast cells, is essential for the expression of ICOS‐L on BMMCs, and costimulation with IL‐3 potentiated the IL‐33‐induced IL‐6 production similar to SCF. In contrast to the enhanced IL‐2 production by SCF‐induced modulation of the IL‐33 signalling, IL‐3 blocked the production of IL‐2. Consequently, IL‐3 shifted the IL‐33‐induced Treg dichotomy towards RORγt+ Tregs at the expense of RORγt− Helios+ Tregs. However, ICOS‐L expression was downregulated by IL‐33. In line with that, ICOS‐L did not play any important role in the Treg modulation by IL‐3/IL‐33‐activated mast cells. These findings demonstrate that different from the mast cell growth factor SCF, IL‐3 can alter the IL‐33‐induced and mast cell‐dependent regulation of Treg subpopulations by modulating mast cell‐derived cytokine profiles.