title: Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells.
abstract: Toll-like receptor (TLR) agonists are considered adjuvants in clinical trials of cancer immunotherapy. Here, we investigated the modulation of gammadelta T cell-mediated tumor cell lysis by TLR ligands. gammadelta T-cell cytotoxicity and granzyme A/B production were enhanced after pretreatment of tumor cells with TLR3 [poly(I:C)] or TLR7 ligand (imiquimod). We examined TLR3- and TLR7-expressing pancreatic adenocarcinomas, squamous cell carcinomas of head and neck and lung carcinomas. Poly(I:C) treatment of pancreatic adenocarcinomas followed by coculture with gammadelta T cells resulted in an upregulation of CD54 on the tumor cells. The interaction of CD54 and the corresponding ligand CD11a/CD18 expressed on gammadelta T cells is responsible for triggering effector function in gammadelta T cells. Moreover, treatment with imiquimod downregulated MHC class I molecules on tumor cells possibly resulting in a reduced binding affinity for inhibitory receptor NKG2A expressed on gammadelta T cells. These results indicate that TLR3 or TLR7 ligand stimulation of tumor cells enhances the cytotoxic activity of expanded gammadelta T cells of cancer patients in vitro.
authors.affiliation: Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Hamed
authors.initials: H
authors.lastname: Shojaei
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.forename: Matthias
authors.initials: M
authors.lastname: Juricke
authors.forename: Lothar
authors.initials: L
authors.lastname: Marischen
authors.forename: Monika
authors.initials: M
authors.lastname: Kunz
authors.forename: Christoph
authors.initials: C
authors.lastname: Mundhenke
authors.forename: Frank
authors.initials: F
authors.lastname: Gieseler
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D000077271:Imiquimod; D009369:Neoplasms / Q000188:drug therapy*; D011070:Poly I-C / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000819:agonists; D051199:Toll-Like Receptor 7 / Q000819:agonists
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D016692:Receptors, Antigen, T-Cell, gamma-delta; C495344:TLR3 protein, human; C495348:TLR7 protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D011070:Poly I-C; D000077271:Imiquimod