title: IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma.
abstract: Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by the accumulation of germinal center-derived malignant B cells engaged in a bidirectional crosstalk with their supportive microenvironment in invaded lymph nodes (LNs) and bone marrow (BM). T follicular helper (TFH) cells and infiltrating stromal cells have been shown to favor FL B-cell growth, but the mechanisms of their protumoral effect and how the LN/BM microenvironment is converted into a lymphoma-permissive cell niche remain poorly understood. We demonstrated here that FL-infiltrating LN and BM stromal cells overexpressed CXCL12 in situ. Interleukin-4 high (IL-4hi) FL-TFHcells, unlike FL B cells themselves, triggered CXCL12 upregulation in human stromal cell precursors. In agreement, expression of CXCL12 was associated with IL-4 expression and signaling within the FL BM and LN niches. This IL-4/CXCL12 axis was amplified in activated lymphoid stromal cells as shown in our in vitro model of human lymphoid stroma differentiation and in an inducible mouse model of ectopic lymphoid organ formation. Finally, CXCL12 triggered primary FL B-cell activation, migration, and adhesion, a process antagonized by BTK and PI3K inhibitors. These data identified the IL-4/CXCL12 loop as a previously unrecognized pathway involved in lymphoid stroma polarization and as a potential therapeutic target in FL patients.
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.
authors.forename: Shubham
authors.initials: S
authors.lastname: Pandey
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.
authors.forename: Frédéric
authors.identifier: 0000-0002-5344-9632
authors.initials: F
authors.lastname: Mourcin
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Centre Hospitalier Universitaire (CHU) de Rennes, Service d'Hématologie Clinique, Rennes, France.
authors.forename: Tony
authors.identifier: 0000-0003-4932-2169
authors.initials: T
authors.lastname: Marchand
authors.affiliation: Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Saba
authors.initials: S
authors.lastname: Nayar
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Guirriec
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|CHU de Rennes, Pôle de Biologie, Rennes, France.
authors.forename: Céline
authors.identifier: 0000-0003-3978-2209
authors.initials: C
authors.lastname: Pangault
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Monvoisin
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|CHU de Rennes, Pôle de Biologie, Rennes, France.
authors.forename: Patricia
authors.identifier: 0000-0001-8042-9250
authors.initials: P
authors.lastname: Amé-Thomas
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guilloton
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|CHU de Rennes, Pôle de Biologie, Rennes, France.
authors.forename: Joelle
authors.initials: J
authors.lastname: Dulong
authors.affiliation: Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Coles
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|CHU de Rennes, Pôle de Biologie, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; and.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.affiliation: UMR U1236, INSERM, Université Rennes 1, Etablissement Français du Sang Bretagne, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|CHU de Rennes, Pôle de Biologie, Rennes, France.
authors.forename: Karin
authors.identifier: 0000-0002-6809-917X
authors.initials: K
authors.lastname: Tarte
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C508598:IL4 protein, human; D015847:Interleukin-4