Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients

• DOI: 10.1007/s00262-010-0887-0
• Publication Date: 2010-06-25T09:25:31Z
• Authors: Florian Cabillic; Olivier Toutirais; Vincent Lavoué; Cécile Thomas de ...; Pascale Daniel; Nathalie Rioux-Le...; Bruno Turlin; Hannu Mönkkönen; Jukka Mönkkönen; Karim Boudjema; Véronique Catros; Françoise Bouet-T...
• Keywords: Cytotoxicity, Immunologic; 0301 basic medicine; MESH: Flow Cytometry; MESH: T-Lymphocyte Subsets; Immunotherapy, Adoptive; MESH: Liver Neoplasms; MESH: Hemiterpenes; MESH: Organophosphorus Compounds; MESH: Carcinoma, Hepatocellular; MESH: Aged; MESH: Middle Aged; MESH: Dendritic Cells; Bone Density Conservation Agents; Diphosphonates; Liver Neoplasms; Imidazoles; Cell Differentiation; Flow Cytometry; 3. Good health; Diphosphates; MESH: Immunotherapy, Adoptive; [SDV.IMM]Life Sciences [q-bio]/Immunology; Female; Colorectal Neoplasms; MESH: Imidazoles; MESH: Cell Differentiation; Carcinoma, Hepatocellular; [SDV.IMM] Life Sciences [q-bio]/Immunology; MESH: Diphosphonates; Blotting, Western; [SDV.CAN]Life Sciences [q-bio]/Cancer; Adenocarcinoma; MESH: Bone Density Conservation Agents; MESH: Coculture Techniques; 03 medical and health sciences; Hemiterpenes; [SDV.CAN] Life Sciences [q-bio]/Cancer; MESH: Receptors, Antigen, T-Cell, gamma-delta; MESH: Cell Proliferation; MESH: Blotting, Western; Humans; MESH: Cytotoxicity, Immunologic; Aged; Cell Proliferation; MESH: Humans; MESH: Adenocarcinoma; Dendritic Cells; MESH: Male; Coculture Techniques; MESH: Diphosphates; MESH: Female; MESH: Colorectal Neoplasms

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.