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Article

CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints

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Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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Health Campus Immunology, Infectiology, and Inflammation (GCI3), Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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ChaMP, Center for Health and Medical Prevention, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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Medical Department 5–Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
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Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
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Laboratory for Experimental Dermatology, Department of Dermatology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: Aksam J. Merched
Cells 2022, 11(14), 2176; https://doi.org/10.3390/cells11142176
Received: 31 May 2022 / Revised: 6 July 2022 / Accepted: 11 July 2022 / Published: 12 July 2022
(This article belongs to the Collection Immuno-Metabolic Crosstalk in Oncogenesis)
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. View Full-Text
Keywords: chronic lymphocytic leukemia; extracellular vesicles; T-cells; immune evasion; immune checkpoints; cellular therapy chronic lymphocytic leukemia; extracellular vesicles; T-cells; immune evasion; immune checkpoints; cellular therapy
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MDPI and ACS Style

Böttcher, M.; Böttcher-Loschinski, R.; Kahlfuss, S.; Aigner, M.; Gießl, A.; Mackensen, A.; Schlötzer-Schrehardt, U.; Tüting, T.; Bruns, H.; Mougiakakos, D. CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints. Cells 2022, 11, 2176. https://doi.org/10.3390/cells11142176

AMA Style

Böttcher M, Böttcher-Loschinski R, Kahlfuss S, Aigner M, Gießl A, Mackensen A, Schlötzer-Schrehardt U, Tüting T, Bruns H, Mougiakakos D. CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints. Cells. 2022; 11(14):2176. https://doi.org/10.3390/cells11142176

Chicago/Turabian Style

Böttcher, Martin, Romy Böttcher-Loschinski, Sascha Kahlfuss, Michael Aigner, Andreas Gießl, Andreas Mackensen, Ursula Schlötzer-Schrehardt, Thomas Tüting, Heiko Bruns, and Dimitrios Mougiakakos. 2022. "CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints" Cells 11, no. 14: 2176. https://doi.org/10.3390/cells11142176

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