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Stem Cells

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

Leukemia volume 24, pages 2080–2089 (2010)Cite this article

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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-STAT6pos 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-TFH 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.

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Acknowledgements

This study was supported by research fundings from the Institut National du Cancer (INCa libre 2005—PL070), the Association pour la Recherche Contre le Cancer (ARC AO 2007), the Ligue Régionale contre le Cancer (AO 2004) and the Association pour le Développement de l’Hémato-Oncologie (ADHO). DR is supported by an INCa fellowship. We thank the ‘Centre de Ressources (CRB)-Santé‘ of Rennes’ hospital, Patrick Tas and Jean-Michel Picquenot for providing non-malignant and follicular lymph nodes, Christophe Ruaux for providing tonsil samples, and the ‘Institut Fédératif de Recherche (IFR)-140’ of Rennes’University for cell sorting core facility.

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Author notes

  1. C Pangault and P Amé-Thomas: These authors contributed equally to this work.

  2. K Tarte and T Fest: These authors contributed equally to this work and are co-corresponding authors.

Authors and Affiliations

  1. Pôle Cellules & Tissus, Centre Hospitalier Universitaire (CHU) Pontchaillou, Rennes, France

    C Pangault, P Amé-Thomas, G Caron, M Roussel, K Tarte & T Fest

  2. INSERM U917, Microenvironnement et Cancer, Université de Rennes 1, Rennes, France

    C Pangault, P Amé-Thomas, G Caron, C Monvoisin, T Lamy, K Tarte & T Fest

  3. INSERM U918, Groupe d’étude des Proliférations Lymphoïdes, Rouen, France

    P Ruminy & H Tilly

  4. INSERM U936, Modélisation conceptuelle des connaissances biomédicales, Université de Rennes 1, Rennes, France

    D Rossille

  5. INSERM U955, Université Paris 12, Créteil, France

    M Baia & P Gaulard

  6. Département de Pathologie, AP-HP, Hôpital Henri Mondor, Créteil, France

    M Baia & P Gaulard

  7. Institut de Recherche en Biothérapie, Hôpital Saint-Eloi, Montpellier, France

    J De Vos

  8. Service d’Hématologie Clinique, CHU Pontchaillou, Rennes, France

    T Lamy

  9. Département d’Hématologie, Centre Henri Becquerel, Rouen, France

    H Tilly

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  1. C Pangault
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Pangault, C., Amé-Thomas, P., Ruminy, P. et al. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent TFH–B cell axis. Leukemia 24, 2080–2089 (2010). https://doi.org/10.1038/leu.2010.223

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