Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class i molecules
Di Franco, Simone
Pangigadde, Pradeepa N.
La Rocca, Rosanna
Di Fabrizio, Enzo M.
KAUST DepartmentPhysical Sciences and Engineering (PSE) Division
Biological and Environmental Sciences and Engineering (BESE) Division
Materials Science and Engineering Program
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AbstractTumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma- derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved.
SponsorsThis work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, as well as by Axel Wenner-Gren Foundation Grant AIRC 10189 (to E. C.) and by Grants AIRC IG 8730 (to G. S.) and AIRC IG 10254 (to M. T.). R. S. is a recipient of a fellowship awarded by the Programma Operativo Regionale Calabria Fondo Sociale Europeo (2007-2013). S. D. F. is a Ph.D. student in the International Ph.D. Program in Immunopharmacology at the University of Palermo. R. T. is a Ph.D. student in the International Ph.D. Program in Molecular Oncology, Experimental Immunology and Development of Innovative Therapies.
PublisherAmerican Association of Immunologists
JournalJournal of Immunology
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