Chemotherapy and Zoledronate Sensitize Solid Tumour Cells to Vgamma9Vdelta2 T Cell Cytotoxicity

Cancer Immunol Immunother. 2007 Aug;56(8):1285-97. doi: 10.1007/s00262-007-0279-2. Epub 2007 Jan 31.

Abstract

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.

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Burkitt Lymphoma / immunology
  • Burkitt Lymphoma / pathology
  • Carcinoma / immunology
  • Carcinoma / pathology
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / immunology
  • Cisplatin / pharmacology
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology
  • Concanavalin A / pharmacology
  • Cytotoxicity, Immunologic / drug effects
  • Diphosphonates / pharmacology*
  • Doxorubicin / pharmacology
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Etoposide / pharmacology
  • Female
  • Genes, T-Cell Receptor delta
  • Genes, T-Cell Receptor gamma
  • Humans
  • Imidazoles / pharmacology*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / metabolism
  • Lovastatin / analogs & derivatives
  • Lovastatin / pharmacology
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Male
  • Membrane Glycoproteins / analysis
  • Neoplasms / immunology
  • Neoplasms / pathology*
  • Perforin
  • Pore Forming Cytotoxic Proteins / analysis
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Urinary Bladder Neoplasms / immunology
  • Urinary Bladder Neoplasms / pathology
  • Vincristine / pharmacology
  • Zoledronic Acid

Substances

  • Antineoplastic Agents
  • Diphosphonates
  • Imidazoles
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • T-cell receptor Vdelta2, human
  • T-cell receptor Vgamma9, human
  • Concanavalin A
  • Perforin
  • mevastatin
  • Vincristine
  • Etoposide
  • Zoledronic Acid
  • Doxorubicin
  • Interferon-gamma
  • Lovastatin
  • Cisplatin