title: Mechanisms of the antitumor activity of human Vγ9Vδ2 T cells in combination with zoledronic acid in a preclinical model of neuroblastoma.
abstract: Low expression of surface major histocompatibility complex (MHC) class I molecules and defects in antigen processing machinery make human neuroblastoma (NB) cells appropriate targets for MHC unrestricted immunotherapeutic approaches. Human T-cell receptor (TCR) Vγ9Vδ2 lymphocytes exert MHC-unrestricted antitumor activity and are activated by phosphoantigens, whose expression in cancer cells is increased by aminobisphosphonates. With this background, we have investigated the in vivo anti-NB activity of human Vγ9Vδ2 lymphocytes and zoledronic acid (ZOL). SH-SY-5Y human NB cells were injected in the adrenal gland of immunodeficient mice. After 3 days, mice received ZOL or human Vγ9Vδ2 T cells or both agents by intravenous administration once a week for 4 weeks. A significantly improved overall survival was observed in mice receiving Vγ9Vδ2 T cells in combination with ZOL. Inhibition of tumor cell proliferation, angiogenesis and lymphangiogenesis, and increased tumor cell apoptosis were detected. Vγ9Vδ2 T lymphocytes were attracted to NB-tumor masses of mice receiving ZOL where they actively modified tumor microenvironment by producing interferon-γ (IFN-γ), that in turn induced CXCL10 expression in NB cells. This study shows that human Vγ9Vδ2 T cells and ZOL in combination inhibit NB growth in vivo and may provide the rationale for a phase I clinical trial in patients with high-risk NB.
authors.affiliation: Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, G. d'Annunzio University, Chieti, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
authors.forename: Paola
authors.initials: P
authors.lastname: Bocca
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cipollone
authors.forename: Fabio
authors.initials: F
authors.lastname: Morandi
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Ignazia
authors.initials: I
authors.lastname: Prigione
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D054357:Chemokine CXCL10; D004164:Diphosphonates; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid; D007371:Interferon-gamma