title: Interleukin-17A promotes the growth of human germinal center derived non-Hodgkin B cell lymphoma.
abstract: Interleukin (IL)-17A belongs to IL-17 superfamily and binds the heterodimeric IL-17 receptor (R)(IL-17RA/IL-17RC). IL-17A promotes germinal center (GC) formation in mouse models of autoimmune or infectious diseases, but the role of IL-17A/IL-17AR complex in human neoplastic GC is unknown. In this study, we investigated expression and function of IL-17A/IL-17AR in the microenvironments of 44 B cell non-Hodgkin lymphomas (B-NHL) of GC origin (15 follicular lymphomas, 17 diffuse large B cells lymphomas and 12 Burkitt lymphomas) and 12 human tonsil GC. Furthermore, we investigated the role of IL-17A in twoin vivomodels of GC B cell lymphoma, generated by s.c. injection of SU-DHL-4 and OCI-Ly8 cell lines in Severe combined immunodeficiency (SCID)/Non Obese Diabetic (NOD) mice. We found that: (i) B-NHL cell fractions and tonsil GC B cells expressed IL-17RA/IL-17RC, (ii) IL-17A signaled in both cell types through NF-kBp65, but not p38, ERK-1/2, Akt or NF-kBp50/105, phosphorylation, (iii) IL-17A was expressed in T cells and mast cells from neoplastic and normal GC microenvironments, (iv) IL-17A rendered tonsil GC B cells competent to migrate to CXCL12 and CXCL13 by downregulating RGS16 expression; (v) IL-17A stimulatedin vitroproliferation of primary B-NHL cells; (vi) IL-17A (1 μg/mouse-per dose) stimulated B-NHL growth in twoin vivomodels by enhancing tumor cell proliferation and neo-angiogenesis. This latter effect depended on IL-17A-mediated induction of pro-angiogenic gene expression in tumor cells and direct stimulation of endothelial cells. These data define a previously unrecognized role of human IL-17A in promoting growth of GC-derived B-NHL and modulating normal GC B cell trafficking.
authors.affiliation: Laboratorio di Oncologia; Istituto Giannina Gaslini ; Genova, Italia.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ferretti
authors.affiliation: Department of Medicine and Sciences of Aging; "G. d'Annunzio" University and Ce.S.I. Aging Research Center; "G. d'Annunzio" University Foundation ; Chieti, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
authors.affiliation: IRCCS AOU San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro ; Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ognio
authors.affiliation: Tumor Immunology Unit; Department of Health Science; Human Pathology Section; University of Palermo ; Palermo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.affiliation: Lymphoma & Genomics Research Program; -IOR- Institute of Oncology Research; and -IOSI- Lymphoma Unit; Oncology Institute of Southern Switzerland ; Bellinzona, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Laboratorio di Oncologia; Istituto Giannina Gaslini ; Genova, Italia.
authors.forename: Anna
authors.initials: A
authors.lastname: Corcione
authors.affiliation: Laboratorio di Oncologia; Istituto Giannina Gaslini ; Genova, Italia.
authors.forename: Ignazia
authors.initials: I
authors.lastname: Prigione
authors.affiliation: Unit of Pathology; IRCCS AOU San Martino -IST- Istituto Nazionale per la Ricerca sul Cancro ; Genova, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fraternali-Orcioni
authors.affiliation: Department of Basic Medical Sciences; Neurosciences and Sensory Organs; University of Bari Medical School ; Bari; Italy ; and National Cancer Institute "Giovanni Paolo II" ; Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Unit of Pathology; IRCCS AOU San Martino -IST- Istituto Nazionale per la Ricerca sul Cancro ; Genova, Italy.
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Ravetti
authors.affiliation: Pathology Unit; Unit of Lymphoid Malignancies; San Raffaele Scientific Institute ; Milano, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Tumor Immunology Unit; Department of Health Science; Human Pathology Section; University of Palermo ; Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Laboratorio di Oncologia; Istituto Giannina Gaslini ; Genova, Italia.
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
keywords: B non-Hodgkin lymphoma; GC B cells; IL-17A; IL-17A receptor; angiogenesis; tumor immunology