title: Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes.
abstract: Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vgamma9Vdelta2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-alpha and IFN-gamma) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vgamma9Vdelta2 T cells to sensitized targets. Vgamma9Vdelta2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vgamma9Vdelta2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Matilde
authors.initials: M
authors.lastname: D'Asaro
authors.forename: Nadia
authors.initials: N
authors.lastname: Caccamo
authors.forename: Flora
authors.initials: F
authors.lastname: Iovino
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Francipane
authors.forename: Serena
authors.initials: S
authors.lastname: Meraviglia
authors.forename: Valentina
authors.initials: V
authors.lastname: Orlando
authors.forename: Carmela
authors.initials: C
authors.lastname: La Mendola
authors.forename: Gaspare
authors.initials: G
authors.lastname: Gulotta
authors.forename: Alfredo
authors.initials: A
authors.lastname: Salerno
authors.forename: Francesco
authors.initials: F
authors.lastname: Dieli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
mesh_terms: D002837:Chromaffin Granules; D003110:Colonic Neoplasms / Q000276:immunology*; D016207:Cytokines; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004164:Diphosphonates / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007167:Immunotherapy; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D014411:Neoplastic Stem Cells / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013729:Terpenes; D000077211:Zoledronic Acid
chemical_list: D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013729:Terpenes; D000077211:Zoledronic Acid