The IL ‐6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B‐cell lymphoma

Hind Hashwah,Anna Stelling,Kristin Stirm,Markus G Manz,Anne Müller,Alexandre P Theocharides,Katrin Bertram,Sabrina Kasser,Alexandar Tzankov,Cheuk‐Ting Wu

doi:10.15252/emmm.201910576

Hind Hashwah, Anna Stelling + Show 8 more

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https://doi.org/10.15252/emmm.201910576

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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.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of the mature B cell
The flow cytometric quantification of DLBCL cell engraftment in the bone marrow of femur and tibia and in jaw bone marrow and spleen revealed that a substantial fraction of leukocytes in both tissues were of human (i.e., DLBCL cell) origin, i.e., hCD45- or hCD19-positive, and had retained their ZsGreen signal during in vivo growth (Fig 1E–G)
In the time frame of up to 6 weeks after tumor cell injection assessed here, DLBCL cell engraftment was accompanied by clinical symptoms in only a small fraction (< 20%) of mice; if they occurred, symptoms included weight loss and progressive paralysis of the hind legs, which in some instances could be attributed to tumor growth in close proximity to the spinal cord

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of the mature B cell. Whereas gene expression profiling has traditionally been used to identify two major subsets of DLBCL that differ in their cell of origin, i.e., the activated B-cell and germinal center B-cell subtypes (ABC- and GCB-DLBCL; Alizadeh et al, 2000; Rosenwald et al, 2002), more recent studies have distinguished up to four (Schmitz et al, 2018) or five (Chapuy et al, 2018) different molecular subtypes based on transcriptional and mutational signatures, somatic copy number alterations, and structural variants. GCB-DLBCL can be stratified into two subtypes, of which one typically harbors translocations juxtaposing BCL2 to the IGH enhancer in combination with frequent mutations of the chromatin modifiers KMT2D, CREBBP, and EZH2, and inactivating PTEN mutations, bears similarities to the genetic landscape of follicular lymphoma and features a poor prognosis, whereas the other is a relatively low-risk subtype with mutations in PI3K-, JAK/STAT-, and MAPK-pathway components and histones (Chapuy et al, 2018; Schmitz et al, 2018)

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