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

Amelie Jaeger, Sudheer Madan Mohan Gambheer, Xiaoyang Sun, Dmitry Chernyakov, Oleksandra Skorobohatko, Thomas 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 KleinThomas Weber, Claudia Wickenhauser, Mascha Binder, Christine Dierks*

*Corresponding author for this work


Peripheral T-cell lymphomas (PTCLs), especially angioimmunoblastic and follicular TCLs, have a dismal prognosis because of the 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 T-cell follicular helper–type PTCL (TFH-PTCL) disease progression and symptoms. We showed that ITK-SYK–driven murine PTCLs and primary human TFH-PTCL xenografts both induced inflammation in mice, including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving interferon gamma (CD4+ malignant T cells) and interleukin 6 (IL-6; activated granulocytes), ultimately inducing broad JAK activation (JAK1/2/3 and TYK2) in both cell types. Inflammatory granulocyte depletion via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox), or IL-6 deletion within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration, and enhanced mouse survival. Furthermore, unselective JAK 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 an intact JAK/STAT signaling pathway for TFH-PTCL development and also support broad JAK inhibition as an effective treatment strategy in early disease stages.

Original languageEnglish
Issue number23
Pages (from-to)2824-2840
Number of pages17
Publication statusPublished - 08.06.2023

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)
  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)


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