The IL‐6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B‐cell lymphoma. Issue 10 (12th September 2019)

• Record Type: Journal Article
• Authors: Hashwah, Hind; Bertram, Katrin; Stirm, Kristin; Stelling, Anna; Wu, Cheuk‐Ting; Kasser, Sabrina; Manz, Markus G; Theocharides, Alexandre P; Tzankov, Alexandar; Müller, Anne
• Is Part Of: EMBO molecular medicine. Volume 11:Issue 10(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-09-12
• Subjects: cancer immunotherapy -- DLBCL mouse models -- lymphoma microenvironment -- oncogenic STAT3 signaling -- personalized treatment; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201910576
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Interleukin‐6 (IL‐6) is a growth factor for normal B cells and plasma cell‐derived malignancies. Here, we show that the IL‐6 signaling pathway is also active in a subset of diffuse large B‐cell lymphoma (DLBCL) patients with particularly poor prognosis. Primary DLBCL cells and DLBCL cell lines expressing IL‐6R engraft and form orthotopic lymphomas in humanized mice that ectopically produce human IL‐6, and in mice reconstituted with a human immune system. We show that a subset of DLBCL cases have evolved mechanisms that ensure constitutive activation of the IL‐6 signaling pathway, i.e., the expression of both chains of the IL‐6R, the expression of the cytokine itself, and the mutational inactivation of a negative regulator of IL‐6 signaling, SOCS1. IL‐6 signaling promotes MYC‐driven lymphomagenesis in a genetically engineered model, and treatment with the IL‐6R‐specific antibody tocilizumab reduces growth of primary DLBCL cells and of DLBCL cell lines in various therapeutic settings. The combined results uncover the IL‐6 signaling pathway as a driver and negative prognosticator in aggressive DLBCL that can be targeted with a safe and well‐tolerated biologic. Synopsis: IL‐6 is a growth factor for B cells and plasma cells, and for a subtype of diffuse large B‐cell lymphoma. The dependence of this subtype on IL‐6 can be exploited for the development of patient‐derived xenograft models, and targeted therapeutically by a monoclonal antibody approved for human use. The IL‐6 signaling pathway was active in a subset of diffuse large B cell lymphomas with a particularly poor prognosis. This subset of DLBCL expressed both chains of the IL‐6 receptor, and either cell‐intrinsically produced IL‐6 or harbored inactivating mutations in the negative regulator SOCS1. Xenotransplantation and genetically engineered mouse models revealed a critical role of IL‐6 signaling in lymphoma cell engraftment and growth. Targeting IL‐6 signaling with tocilizumab reduced DLBCL growth in cell line xenotransplantation and patient‐derived xenograft models. Abstract : IL‐6 is a growth factor for B cells and plasma cells, and for a subtype of diffuse large B‐cell lymphoma. The dependence of this subtype on IL‐6 can be exploited for the development of patient‐derived xenograft models, and targeted therapeutically by a monoclonal antibody approved for human use.