title: Activated iNKT cells promote Vγ9Vδ2-T cell anti-tumor effector functions through the production of TNF-α.
abstract: Vγ9Vδ2-T cells constitute a proinflammatory lymphocyte subpopulation with established antitumor activity. Phosphoantigens activate Vγ9Vδ2-T cells in vivo and in vitro. We studied whether the antitumor activity of Vγ9Vδ2-T cells can be potentiated by invariant NKT cells (iNKT), an important immunoregulatory T cell subset. When activated by the glycolipid α-galactosylceramide (α-GalCer), iNKT produce large amounts of cytokines involved in antitumor immune responses. Monocyte-derived dendritic cells were loaded with both phosphoantigens (using aminobisphosphonates) and α-GalCer during maturation and subsequently co-cultured with Vγ9Vδ2-T and iNKT cells. Aminobisphosphonates dose-dependently enhanced Vγ9Vδ2-T cell activation, and this was potentiated by α-GalCer-induced iNKT co-activation. iNKT co-activation also enhanced the IFN-γ production and cytolytic potential of Vγ9Vδ2-T cells against tumor cells. Using transwell experiments and neutralizing antibodies cross-talk between iNKT and Vγ9Vδ2-T cells was found to be mediated by TNF-α. Our data provide a rationale for combining both activating ligands to improve Vγ9Vδ2-T cell based approaches in cancer-immunotherapy.
authors: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. f.schneiders@vumc.nl
authors: Famke L
authors: FL
authors: Schneiders
authors: Renée C G
authors: RC
authors: de Bruin
authors: Saskia J A M
authors: SJ
authors: Santegoets
authors: Marc
authors: M
authors: Bonneville
authors: Emmanuel
authors: E
authors: Scotet
authors: Rik J
authors: RJ
authors: Scheper
authors: Henk M W
authors: HM
authors: Verheul
authors: Tanja D
authors: TD
authors: de Gruijl
authors: Hans J
authors: HJ
authors: van der Vliet
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology; D045782:Hemiterpenes / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009943:Organophosphorus Compounds / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D004164:Diphosphonates; D005699:Galactosylceramides; D045782:Hemiterpenes; D007155:Immunologic Factors; D009943:Organophosphorus Compounds; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; C004809:isopentenyl pyrophosphate; D007371:Interferon-gamma