The immunometabolic reprogramming of human T-cells by chronic lymphocytic leukemia-derived exosomes
Final Report Abstract
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults in the western world, primarily affecting older individuals (median age of diagnosis: 72 years), with approximately 2500 new cases diagnosed annually in Germany alone. CLL is characterized by the clonal expansion of malignant B cells with aberrant B cell receptor (BCR) signaling and defective apoptotic mechanisms. These malignanT-cells circulate in the peripheral blood and infiltrate the spleen and lymph nodes, resulting in lymphocytosis, splenomegaly and lymphadenopathy. Treatment of CLL varies depending on the stage, dynamics, prognostic markers and overall health of the patient, ranging from watchful waiting to chemo-immunotherapy and targeted therapies such as ibrutinib and venetoclax. Allogeneic stem cell transplantation offers a potential cure, but is associated with significant risks that limit its applicability in elderly patients with comorbidities. CLL is also characterized by immune defects that result in increased susceptibility to infection and ineffective antitumor immune responses. These immune defects result from complex interactions between malignanT-cells and the tumor microenvironment. In CLL patients, T-cells exhibit numerical, phenotypic, and functional abnormalities such as skewed CD4/CD8 ratios, exhaustion and accumulation of immunosuppressive regulatory FOXP3+ CD4+ T-cells (Tregs). Importantly, similar changes were observed in healthy donor (HD) T-cells cultured in the presence of CLL cells, demonstrating the immunomodulatory capacity of CLL cells. Recent studies have also highlighted metabolic defects in T-cells mediated by CLL cells, in particular a failure to upregulate aerobic glycolysis upon activation, which is essential for efficient T-cell activation. Modulation of T-cell metabolism has therefore emerged as a promising avenue for controlling immune responses, with potential implications for cancer immunotherapy. Extracellular vesicles (EVs) have emerged as key players in cellular crosstalk. CLL cells constitutively release EVs loaded with biologically active molecules. Understanding the impact of CLL-derived EVs on T-cells provides insight into the immune deficiencies associated with CLL. In addition, it highlights the potential of immunotherapeutic approaches to counteract these effects, providing new avenues for CLL treatment. Our research has shown that CLL-EVs have a detrimental effect on T-cell viability, proliferation, activation and metabolism. At the same time, they facilitate T-cell exhaustion and the emergence of regulatory T-cell subsets. An indepth study of CLL-EVs revealed a significant presence of immunological checkpoints (ICs), which may explain the observed T-cell dysregulations and provide an approach to enhance anti-tumor immune responses by targeting EV formation and multiple ICs simultaneously.
Publications
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Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling. Cancer Research, 80(17), 3663-3676.
Tohumeken, Sehmus; Baur, Rebecca; Böttcher, Martin; Stoll, Andrej; Loschinski, Romy; Panagiotidis, Konstantinos; Braun, Martina; Saul, Domenica; Völkl, Simon; Baur, Andreas S.; Bruns, Heiko; Mackensen, Andreas; Jitschin, Regina & Mougiakakos, Dimitrios
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Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis. Journal for ImmunoTherapy of Cancer, 9(4), e001889.
Böttcher, Martin; Bruns, Heiko; Völkl, Simon; Lu, Junyan; Chartomatsidou, Elisavet; Papakonstantinou, Nikos; Mentz, Kristin; Büttner-Herold, Maike; Zenz, Thorsten; Herling, Marco; Huber, Wolfgang; Ghia, Paolo; Stamatopoulos, Kostas; Mackensen, Andreas & Mougiakakos, Dimitrios
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Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia. Nature Cancer, 2(8), 853-864.
Lu, Junyan; Cannizzaro, Ester; Meier-Abt, Fabienne; Scheinost, Sebastian; Bruch, Peter-Martin; Giles, Holly A. R.; Lütge, Almut; Hüllein, Jennifer; Wagner, Lena; Giacopelli, Brian; Nadeu, Ferran; Delgado, Julio; Campo, Elías; Mangolini, Maurizio; Ringshausen, Ingo; Böttcher, Martin; Mougiakakos, Dimitrios; Jacobs, Andrea; Bodenmiller, Bernd ... & Huber, Wolfgang
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“Moonlighting” at the power plant: how mitochondria facilitate serial killing by CD8+ cytotoxic T cells. Signal Transduction and Targeted Therapy, 6(1).
Mougiakakos, Dimitrios & Kahlfuss, Sascha
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CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints. Cells, 11(14), 2176.
Böttcher, Martin; Böttcher-Loschinski, Romy; Kahlfuss, Sascha; Aigner, Michael; Gießl, Andreas; Mackensen, Andreas; Schlötzer-Schrehardt, Ursula; Tüting, Thomas; Bruns, Heiko & Mougiakakos, Dimitrios
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Accumulation of T-cell-suppressive PD-L1high extracellular vesicles is associated with GvHD and might impact GvL efficacy. Journal for ImmunoTherapy of Cancer, 11(3), e006362.
Baur, Rebecca; Karl, Franziska; Böttcher-Loschinski, Romy; Stoll, Andrej; Völkl, Simon; Gießl, Andreas; Flamann, Cindy; Bruns, Heiko; Schlötzer-Schrehardt, Ursula; Böttcher, Martin; Schewe, Denis M.; Fischer, Thomas; Jitschin, Regina; Mackensen, Andreas & Mougiakakos, Dimitrios
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DGHO conference meeting in 2022, Session “Chronische Leukämien”: „V40 Extrazelluläre Vesikel von CLL-Zellen beeinträchtigen die T-Zell-Aktivierung und begünstigen deren Erschöpfung mittels diverser immunologischer Checkpoints”
Martin Böttcher
