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RESEARCH PRODUCT

Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes

M TodaroM D'asaroN CaccamoF IovinoMg FrancipaneS MeravigliaValentina OrlandoC La MendolaG GulottaA SalernoF DieliG. Stassi

subject

Cytotoxicity ImmunologicDiphosphonatesTerpenesT-LymphocytesImidazolesReceptors Antigen T-Cell gamma-deltaZoledronic AcidColon cancer stem cells gamma delta T cellsNK Cell Lectin-Like Receptor Subfamily KColonic NeoplasmsNeoplastic Stem CellsCytokinesHumansChromaffin GranulesImmunotherapy

description

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.

10.4049/jimmunol.0804288http://hdl.handle.net/10447/37822