title: Immune modulation by zoledronic acid in human myeloma: an advantageous cross-talk between Vγ9Vδ2 T cells, αβ CD8+ T cells, regulatory T cells, and dendritic cells.
abstract: Vγ9Vδ2 T cells play a major role as effector cells of innate immune responses against microbes, stressed cells, and tumor cells. They constitute <5% of PBLs but can be expanded by zoledronic acid (ZA)-treated monocytes or dendritic cells (DC). Much less is known about their ability to act as cellular adjuvants bridging innate and adaptive immunity, especially in patients with cancer. We have addressed this issue in multiple myeloma (MM), a prototypic disease with several immune dysfunctions that also affect γδ T cells and DC. ZA-treated MM DC were highly effective in activating autologous γδ T cells, even in patients refractory to stimulation with ZA-treated monocytes. ZA inhibited the mevalonate pathway of MM DC and induced the intracellular accumulation and release into the supernatant of isopentenyl pyrophosphate, a selective γδ T cell activator, in sufficient amounts to induce the proliferation of γδ T cells. Immune responses against the tumor-associated Ag survivin (SRV) by MHC-restricted, SRV-specific CD8(+) αβ T cells were amplified by the concurrent activation of γδ T cells driven by autologous DC copulsed with ZA and SRV-derived peptides. Ancillary to the isopentenyl pyrophosphate-induced γδ T cell proliferation was the mevalonate-independent ZA ability to directly antagonize regulatory T cells and downregulate PD-L2 expression on the DC cell surface. In conclusion, ZA has multiple immune modulatory activities that allow MM DC to effectively handle the concurrent activation of γδ T cells and MHC-restricted CD8(+) αβ antitumor effector T cells.
authors.affiliation: Laboratorio di Ematologia Oncologica, Centro di Ricerca in Medicina Sperimentale, 10126 Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Castella
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiore
authors.forename: Francesca
authors.initials: F
authors.lastname: Pantaleoni
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Canepari
authors.forename: Silvia
authors.initials: S
authors.lastname: Peola
authors.forename: Myriam
authors.initials: M
authors.lastname: Foglietta
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
authors.forename: Marta
authors.initials: M
authors.lastname: Coscia
authors.forename: Mario
authors.initials: M
authors.lastname: Boccadoro
authors.forename: Massimo
authors.initials: M
authors.lastname: Massaia
mesh_terms: D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D004164:Diphosphonates / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D045782:Hemiterpenes / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008798:Mevalonic Acid / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology*; D009943:Organophosphorus Compounds / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D000077211:Zoledronic Acid
chemical_list: D018122:B7-1 Antigen; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D009943:Organophosphorus Compounds; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D008798:Mevalonic Acid