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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.

Ruxolitinib (Jakavi) is a potent JAK1/JAK2 specific inhibitor, approved for the treatment of myeloproliferative neoplasia (MPN) such as primary myelofibrosis (PMF) and polycythemia Vera (PV). The primary clinical benefit of ruxolitinib in MPN patients is reduction in spleen size and alleviation of constitutional symptoms and significant improvement in the quality of life. However, the effect of ruxolitinib on bone marrow fibrosis and JAK2V617F allelic burden is modest. In addition, JAK2V617F negative MPNs also demonstrated clinical benefits, thus, is not clear whether the ruxolitinib primarily blocks the proliferation of the malignant clone or exerts its effects by targeting non-malignant cells. To gain the mechanism of ruxolitinib action in MPNs, we developed two JAK2V617F-driven MPN mouse models harboring ruxolitinib resistant mutations JAK2V617F+L902Q and JAK2V617F+L983F in the malignant clone. Similar to JAK2V617F recipients, JAK2V617F+L902Q and JAK2V617F+L983F transplanted mice showed an increase in WBC, HCT, RBC, HB and reticulocyte values. Histopathological analysis revealed that the myeloproliferative phenotype resembles PV with a proliferation of all three lineages albeit with only a moderate increase in megakaryopoeisis. Grade II bone marrow fibrosis was observed in JAK2V617F+L902Q and JAK2V617F+L983F after 2-3 months similar to JAK2V617F mice. Surprisingly, these mice respond to ruxolitinib treatment similar to ruxolitinib sensitive JAK2V617F mice, indicated by reduction of spleen size, leukocyte count and proinflammatory cytokines in the serum. Mechanistically, we could identify a direct role of ruxolitinib in the impairment of inflammatory processes in the bone marrow microenvironment, particularly on the cytokine production of mesenchymal stem cells and endothelial cells. These results suggest that the ruxolitinib mediated effects in MPN patients are mainly due to abrogation of inflammatory signaling processes in non-malignant cells. Therefore, combination treatment of JAK1/2 inhibitors with novel inhibitors, which specifically act on malignant cells might improve the clinical benefit for MPN patients to JAK family inhibitors. Citation Format: Sivahari Prasad Gorantla, Michael Rassner Rassner, Tony Andreas Müller, Teresa Poggio, Kirstyn Anne Crossley, Anna-Lena Denecke, Kornelia R Fritsch, Geoffroy Andrieux, Helen Kleinfelder, Shifa Khaja Saleem, Sudheer Madan Mohan Gambheer, Irene Gonzalez Menendez, Detlef Bentrop, Rainer Trittler, Svetlana Rylova, Dietmar Pfeifer, Leticia Quintanilla Martinez, Christine Dierks, Robert Zeiser, Anna Lena Illert, Nikolas von Bubnoff, Justus Duyster. Efficacy of Jak1/2 inhibition in murine myeloproliferative neoplasms is mediated by targeting nonmalignant cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4497.

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