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T Lymphocytes1
* Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy;
Department of Biopathology and Biomedical Methodologies, University of Palermo, Palermo, Italy; and
Department of Emergency General Surgery and Organ Transplants, University of Palermo, Palermo, Italy
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 V
9V
2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-
and IFN-) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of V9V2 T cells to sensitized targets. V9V2 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 V9V2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by PRIN Grant 2006068412-002 (to F.D.), by Associazione Italiana per la Ricerca sul Cancro grants (to M.T.), and by Istituto Superiore di Sanità Oncoproteomic Project 2007-527/B/3A/3 (to G.S. and F.D.). M.G.F. and V.O. are Ph.D. students of the International Ph.D. Programme in Immunopharmacology at the University of Palermo.
2 F.D. and G.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Francesco Dieli, Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, 90134 Palermo, Italy. E-mail address: dieli{at}unipa.it
4 Abbreviations used in this paper: CSC, cancer stem cell; FasL, Fas ligand; N-BP, aminobisphosphonate; BLT, N-carbobenzoxy-L-lysine-thiobenzyl; IPP, isopentenyl pyrophosphate; EF, expansion factor; CMA, concanamycin A; ESA, epithelial-specific Ag; MIC, major histocompatibility complex class I-related molecules; PI, propidium iodide.
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