Chemotherapy and zoledronate sensitize solid tumour cells to Vgamma9Vdelta2 T cell cytotoxicity.
Combinations of cellular immune-based therapies with chemotherapy and other antitumour agents may be of significant clinical benefit in the treatment of many forms of cancer. Gamma delta (gammadelta) T cells are of particular interest for use in such combined therapies due to their potent antitumour cytotoxicity and relative ease of generation in vitro. Here, we demonstrate high levels of cytotoxicity against solid tumour-derived cell lines with combination treatment utilizing Vgamma9Vdelta2 T cells, chemotherapeutic agents and the bisphosphonate, zoledronate. Pre-treatment with low concentrations of chemotherapeutic agents or zoledronate sensitized tumour cells to rapid killing by Vgamma9Vdelta2 T cells with levels of cytotoxicity approaching 90%. In addition, zoledronate enhanced the chemotherapy-induced sensitization of tumour cells to Vgamma9Vdelta2 T cell cytotoxicity resulting in almost 100% lysis of tumour targets in some cases. Vgamma9Vdelta2 T cell cytotoxicity was mediated by perforin following TCR-dependent and isoprenoid-mediated recognition of tumour cells. Production of IFN-gamma by Vgamma9Vdelta2 T cells was also induced after exposure to sensitized targets. We conclude that administration of Vgamma9Vdelta2 T cells at suitable intervals after chemotherapy and zoledronate may substantially increase antitumour activities in a range of malignancies.
Mattarollo
Stephen R
SR
Centre for Immune and Targeted Therapy, University of Queensland, Brisbane, QLD, Australia. s364258@student.uq.edu.au
Kenna
Tony
T
Nieda
Mie
M
Nicol
Andrew J
AJ
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D002051:Burkitt Lymphoma / Q000276:immunology / Q000473:pathology; D002277:Carcinoma / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000276:immunology; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology; D003208:Concanavalin A / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D019676:Genes, T-Cell Receptor delta; D019675:Genes, T-Cell Receptor gamma; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000032:analysis; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D003208:Concanavalin A; D054353:Perforin; C012258:mevastatin; D014750:Vincristine; D005047:Etoposide; D000077211:Zoledronic Acid; D004317:Doxorubicin; D007371:Interferon-gamma; D008148:Lovastatin; D002945:Cisplatin