TY  - JOUR
AU  - Jaeger, Amelie
AU  - Gambheer, Sudheer Madan Mohan
AU  - Sun, Xiaoyang
AU  - Chernyakov, Dmitry
AU  - Skorobohatko, Oleksandra
AU  - Mack, Thomas M
AU  - Kissel, Sandra
AU  - Pfeifer, Dietmar
AU  - Zeiser, Robert
AU  - Fisch, Paul
AU  - Andrieux, Geoffroy
AU  - Bräuer-Hartmann, Daniela
AU  - Bauer, Marcus
AU  - Schulze, Susann
AU  - Follo, Marie
AU  - Börries, Melanie
AU  - von Bubnoff, Nikolas
AU  - Miething, Cornelius
AU  - Hidalgo, Jose Villacorta
AU  - Klein, Claudius
AU  - Weber, Thomas
AU  - Wickenhauser, Claudia
AU  - Binder, Mascha
AU  - Dierks, Christine
TI  - Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms.
JO  - Blood
VL  - 141
IS  - 23
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2023-00186
SP  - 2824-2840
PY  - 2023
N1  - 2023 Jun 8;141(23):2824-2840
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36696631
DO  - DOI:10.1182/blood.2022015653
UR  - https://inrepo02.dkfz.de/record/212478
ER  -