Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms.
Amelie JaegerSudheer Madan Mohan GambheerXiaoyang SunDmitry ChernyakovOleksandra SkorobohatkoThomas M MackSandra KisselDietmar PfeiferRobert ZeiserPaul FischGeoffroy AndrieuxDaniela Bräuer-HartmannMarcus BauerSusann SchulzeMarie FolloMelanie BörriesNikolas von BubnoffChristoph Cornelius MiethingJose Villacorta HidalgoClaudius KleinThomas WeberClaudia WickenhauserMascha BinderChristine DierksPublished in: Blood (2023)
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.
Keyphrases
- oxidative stress
- peripheral blood
- induced apoptosis
- signaling pathway
- end stage renal disease
- sleep quality
- weight loss
- tyrosine kinase
- diabetic rats
- diffuse large b cell lymphoma
- ejection fraction
- newly diagnosed
- mouse model
- epithelial mesenchymal transition
- recombinant human
- peritoneal dialysis
- endothelial cells
- chronic kidney disease
- bariatric surgery
- stem cells
- body mass index
- gene expression
- cell therapy
- single cell
- drug induced
- cell proliferation
- dna methylation
- cell cycle arrest
- roux en y gastric bypass
- single molecule
- regulatory t cells
- wound healing
- obese patients
- stress induced
- induced pluripotent stem cells