title: Aminobisphosphonate-pretreated dendritic cells trigger successful Vgamma9Vdelta2 T cell amplification for immunotherapy in advanced cancer patients.
abstract: Hepatocellular carcinoma (HCC) and colorectal carcinoma with hepatic metastases (mCRC) are cancers with poor prognosis and limited therapeutic options. New approaches are needed and adoptive immunotherapy with Vgamma9Vdelta2 T lymphocytes represents an attractive strategy. Indeed, Vgamma9Vdelta2 T cells were shown to exhibit efficient lytic activity against various human tumor cell lines, and in vitro Vgamma9Vdelta2 T expansion protocol based on single phosphoantigen stimulation could be easily performed for healthy donors. However, a low proliferative response of Vgamma9Vdelta2 T cells was observed in about half of the cancer patients, leading to an important limitation in the development of Vgamma9Vdelta2 T cell-based immunotherapy. Here, for the first time in the context of cancer patients, Vgamma9Vdelta2 T cell expansions were performed by co-culturing peripheral blood mononuclear cell (PBMCs) with autologous dendritic cells (DCs) pretreated with aminobisphosphonate zoledronate. For patients not responding to the conventional culture protocol, co-culture of PBMC with zoledronate-pretreated DCs induced strong cell expansion and allowed reaching a minimal rate of purity of 70% of Vgamma9Vdelta2 T cells. The potent immunostimulatory activity of zoledronate-treated DCs was associated with higher amount of isopentenyl pyrophosphate (IPP) in the culture and was correlated with better ability to activate Vgamma9Vdelta2 T cells as measured by IFN-gamma production. Moreover, we demonstrated that the cytotoxic level of Vgamma9Vdelta2 T cells against freshly autologous tumor cells isolated from patients could be significantly increased by pretreating the tumor cells with zoledronate. Thus, this method of generating Vgamma9Vdelta2 T cells leads eligible for Vgamma9Vdelta2 T cell adoptive immunotherapy the HCC and mCRC patients.
authors.affiliation: EE341 Biothérapies Innovantes, Faculté de Médecine, Université de Rennes 1, Rennes, France. florian.cabillic@univ-rennes1.fr
authors.forename: Florian
authors.initials: F
authors.lastname: Cabillic
authors.forename: Olivier
authors.initials: O
authors.lastname: Toutirais
authors.forename: Vincent
authors.initials: V
authors.lastname: Lavoué
authors.forename: Cécile Thomas
authors.initials: CT
authors.lastname: de La Pintière
authors.forename: Pascale
authors.initials: P
authors.lastname: Daniel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux-Leclerc
authors.forename: Bruno
authors.initials: B
authors.lastname: Turlin
authors.forename: Hannu
authors.initials: H
authors.lastname: Mönkkönen
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: Karim
authors.initials: K
authors.lastname: Boudjema
authors.forename: Véronique
authors.initials: V
authors.lastname: Catros
authors.forename: Françoise
authors.initials: F
authors.lastname: Bouet-Toussaint
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000368:Aged; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D049109:Cell Proliferation; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D011756:Diphosphates / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D045782:Hemiterpenes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D011756:Diphosphates; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C429553:bromohydrin pyrophosphate; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid