Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms

Autor: Amelie Jaeger, Sudheer Madan Mohan Gambheer, Xiaoyang Sun, Dmitry Chernyakov, Oleksandra Skorobohatko, Thomas M. Mack, Sandra Kissel, Dietmar Pfeifer, Robert Zeiser, Paul Fisch, Geoffroy Andrieux, Daniela Bräuer-Hartmann, Marcus Bauer, Susann Schulze, Marie Follo, Melanie Boerries, Nikolas von Bubnoff, Cornelius Miething, Jose Villacorta Hidalgo, Claudius Klein, Thomas Weber, Claudia Wickenhauser, Mascha Binder, Christine Dierks
Rok vydání: 2023
Předmět:
Zdroj: Blood.
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.2022015653
Popis: Peripheral T-cell lymphomas (PTCL) - especially angioimmunoblastic (AITL) and follicular TCL - have a dismal prognosis due to lack of efficient therapies, and patients` symptoms are often dominated by an inflammatory phenotype including fever, night sweats, weight loss and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on PTCL-TFH (T-follicular helper type) disease progression and symptoms. We show, that ITK-SYK driven murine PTCLs and primary human PTCL-TFH xenografts both induce inflammation in mice including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving INF-γ (CD4+malignant T-cells) and IL-6 (activated granulocytes), ultimately inducing broad JAK kinase activation (Jak1/2/3, Tyk2) in both cell types. Depletion of inflammatory granulocytes via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox) or the deletion of IL-6 within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration and enhanced mouse survival. Furthermore, unselective JAK kinase inhibitors (ruxolitinib) inhibited both, TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions and the requirement of an intact JAK/STAT signaling pathway for PTCL-TFH development, and support broad JAK kinase inhibition as an effective treatment strategy in early disease stages.
Databáze: OpenAIRE
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