title: Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vδ 2 T lymphocytes in non-Hodgkin lymphomas.
abstract: In this study, we analyzed the influence of mesenchymal stromal cells derived from lymph nodes of non-Hodgkin's lymphomas, on effector functions and differentiation of Vdelta (δ)2 T lymphocytes. We show that: i) lymph-node mesenchymal stromal cells of non-Hodgkin's lymphoma inhibit NKG2D-mediated lymphoid cell killing, but not rituximab-induced antibody-dependent cell-mediated cytotoxicity, exerted by Vδ2 T lymphocytes; ii) pre-treatment of mesenchymal stromal cells with the aminobisphosphonates pamidronate or zoledronate can rescue lymphoma cell killing via NKG2D; iii) this is due to inhibition of transforming growth factor-β and increase in interleukin-15 production by mesenchymal stromal cells; iv) aminobisphosphonate-treated mesenchymal stromal cells drive Vδ2 T-lymphocyte differentiation into effector memory T cells, expressing the Thelper1 cytokines tumor necrosis factor-α and interferon-γ. In non-Hodgkin's lymphoma lymph nodes, Vδ2 T cells were mostly naïve; upon co-culture with autologous lymph-node mesenchymal stromal cells exposed to zoledronate, the percentage of terminal differentiated effector memory Vδ2 T lymphocytes increased. In all non-Hodgkin's lymphomas, low or undetectable transcription of Thelper1 cytokines was found. In diffused large B-cell lymphomas and in a group of follicular lymphoma, transcription of transforming growth factor β and interleukin-10 was enhanced compared to non-neoplastic lymph nodes. Thus, in non-Hodgkin lymphomas mesenchymal stromal cells interfere with Vδ2 T-lymphocyte cytolytic function and differentiation to Thelper1 and/or effector memory cells, depending on the prominent in situ cytokine milieu. Aminobisphosphonates, acting on lymph-node mesenchymal stromal cells, can push the balance towards Thelper1/effector memory and rescue the recognition and killing of lymphoma cells through NKG2D, sparing rituximab-induced antibody-dependent cell-mediated cytotoxicity.
authors.affiliation: alessandro.poggi@istge.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musso
authors.forename: Silvia
authors.initials: S
authors.lastname: Catellani
authors.forename: Paolo
authors.initials: P
authors.lastname: Canevali
authors.forename: Sara
authors.initials: S
authors.lastname: Tavella
authors.forename: Roberta
authors.initials: R
authors.lastname: Venè
authors.forename: Silvia
authors.initials: S
authors.lastname: Boero
authors.forename: Ivana
authors.initials: I
authors.lastname: Pierri
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Kunkl
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ravetti
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D004164:Diphosphonates; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta