Follicular lymphoma cell niche: Identification of a preeminent IL-4-dependent TFH-B cell axis

Abstract

Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained from whole biopsy samples, have been associated with patient survival. In this study, we performed gene expression profiling of purified B cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 non-redundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an interleukin-4 (IL-4)-centered pathway associated with an activation of signal transducer and activator of transcription 6 (STAT6), which favors overexpression of IL-4-target genes. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (TFH), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6 pos B cells were located at the vicinity of cells expressing the programmed death 1 (PD-1) TFH marker. Moreover, purified FL-derived TFH, expressed IL4 at very high levels compared with purified tonsil-derived TFH or non-T FH microenvironment. Altogether, our study demonstrated that tumor-infiltrating TFH specifically express functional IL-4 in FL, creating an IL-4-dependent TFH-B cell axis. This cross talk could sustain FL pathogenesis and represent a new potential therapeutic target. © 2010 Macmillan Publishers Limited All rights reserved.