title: Neutrophils trigger a NF-κB dependent polarization of tumor-supportive stromal cells in germinal center B-cell lymphomas.
abstract: Both tumor-associated neutrophils (TAN) and cancer-associated fibroblasts (CAFs) display specific phenotypic and functional features and contribute to tumor cell niche. However, their bidirectional crosstalk has been poorly studied, in particular in the context of hematological malignancies. Follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL) are two germinal center-derived lymphomas where various cell components of infiltrating microenvironment, including TAN and CAFs, have been demonstrated to favor directly and indirectly malignant B-cell survival, growth, and drug resistance. We show here that, besides a direct and contact-dependent supportive effect of neutrophils on DLBCL B-cell survival, mediated through the BAFF/APRIL pathway, neutrophils and stromal cells cooperate to sustain FL B-cell growth. This cooperation relies on an overexpression of IL-8 by lymphoma-infiltrating stromal cells that could thereafter efficiently promote neutrophil survival and prime them to neutrophil extracellular trap. Conversely, neutrophils are able to activate stromal cells in a NF-κB-dependent manner, inducing their commitment towards an inflammatory lymphoid stroma phenotype associated with an increased capacity to trigger malignant B-cell survival, and to recruit additional monocytes and neutrophils through the release of CCL2 and IL-8, respectively. Altogether, a better understanding of the lymphoma-supporting effects of neutrophils could be helpful to design new anti-tumor therapeutic strategies.
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Grégoire
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guilloton
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.|CHU de Rennes, Pôle Biologie, Rennes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Pangault
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mourcin
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.|CHU de Rennes, Service de Médecine de L'enfant et de L'adolescent, Rennes, France.
authors.forename: Phaktra
authors.initials: P
authors.lastname: Sok
authors.affiliation: EFS Bretagne, Rennes, France.|CHU de Rennes, Pôle Biologie, Rennes, France.
authors.forename: Maelle
authors.initials: M
authors.lastname: Latour
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.|CHU de Rennes, Pôle Biologie, Rennes, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Amé-Thomas
authors.affiliation: CHU de Rennes, Service de Chirurgie Thoracique et Cardiovasculaire, Rennes, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Flecher
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.|CHU de Rennes, Pôle Biologie, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.affiliation: INSERM, UMR U917, Equipe Labellisée Ligue Contre le Cancer, Rennes, France.|Université Rennes 1, UMR917, Rennes, France.|EFS Bretagne, Rennes, France.|CHU de Rennes, Pôle Biologie, Rennes, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D002648:Child; D065206:Extracellular Traps / Q000276:immunology; D005347:Fibroblasts / Q000378:metabolism*; D018858:Germinal Center; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000276:immunology / Q000473:pathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D053264:B-Cell Activating Factor; C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C505719:TNFSF13B protein, human; D051550:I-kappa B Kinase
keywords: B-cell lymphoma; cell differentiation; cell interaction; lymph node; tumor microenvironment