The IL-6 signaling axis is a critical driver and therapeutic target in diffuse large B-cell lymphoma

Interleukin-6 (IL-6) is a growth factor for normal B-cells and plasma cell-derived malignancies. Here we show that the IL-6 signalling 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 signalling 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 signalling, SOCS1. IL-6 signalling 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 signalling pathway as a driver and negative prognosticator in aggressive DLBCL that can be targeted with a safe and well-tolerated biologic.