title: Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy.
abstract: The prognosis of follicular lymphoma (FL) patients is suspected to be influenced by tumor-infiltrating regulatory T cells (Treg). The mechanism of Treg enrichment in FL and their impact on malignant FL B cells remains to be elucidated. We analyzed 46 fresh lymph node biopsy samples, including FL (n = 20), diffuse large B-cell lymphoma (n = 10), classical Hodgkin lymphoma (n = 9), and reactive lymphadenitis (n = 7). Using multicolor flow cytometry and cell sorting, we observed an accumulation of CD25(high)CD127(low/neg) Tregs in FL tissues. These Tregs comprised activated ICOS(+) Tregs that were able to suppress not only conventional T cells, but also FL B cells. These FL B cells were able to express ICOSL in vitro and to generate CD25(high)FoxP3(high) Tregs expressing ICOS. Treg generation was associated with ICOS/ICOSL engagement and was abrogated by antagonist anti-ICOS and anti-ICOSL antibodies. Interactions between Tregs and FL B cells resulted in ICOSL downregulation on FL B cells. Our results highlight a key role for Tregs in FL pathogenesis and suggest that targeting the ICOS/ICOSL pathway may be a promising immunotherapy for FL treatment. Cancer Res; 76(16); 4648-60. ©2016 AACR.
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France. Aix Marseille Université, Marseille, France.
authors.forename: Kieu-Suong
authors.initials: KS
authors.lastname: Le
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France. Institut Paoli - Calmettes, Marseille, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Thibult
authors.affiliation: Institut Paoli - Calmettes, Marseille, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Just-Landi
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pastor
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Gondois-Rey
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Granjeaud
authors.affiliation: Institut Paoli - Calmettes, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Broussais
authors.affiliation: Institut Paoli - Calmettes, Marseille, France.
authors.forename: Reda
authors.initials: R
authors.lastname: Bouabdallah
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052/CNRS 5286, Lyon, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Colisson
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052/CNRS 5286, Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052/CNRS 5286, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Ménétrier-Caux
authors.affiliation: Institut Albert Bonniot, Grenoble, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France. Aix Marseille Université, Marseille, France. Institut Paoli - Calmettes, Marseille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Xerri
authors.affiliation: Centre de recherche en Cancérologie de Marseille, Inserm U1068/CNRS U7258, Marseille, France. Aix Marseille Université, Marseille, France. Institut Paoli - Calmettes, Marseille, France. daniel.olive@inserm.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000037:antagonists & inhibitors / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000037:antagonists & inhibitors / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C556692:ICOS protein, human; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein