Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules.
Tumor 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.
Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100 Catanzaro, Italy.
Rossana
R
Tallerico
Matilde
M
Todaro
Simone
S
Di Franco
Cristina
C
Maccalli
Cinzia
C
Garofalo
Rosa
R
Sottile
Camillo
C
Palmieri
Luca
L
Tirinato
Pradeepa N
PN
Pangigadde
Rosanna
R
La Rocca
Ofer
O
Mandelboim
Giorgio
G
Stassi
Enzo
E
Di Fabrizio
Giorgio
G
Parmiani
Alessandro
A
Moretta
Francesco
F
Dieli
Klas
K
Kärre
Ennio
E
Carbone
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D019070:Cell Lineage / Q000276:immunology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000235:genetics / Q000276:immunology*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology*; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D009928:Organ Specificity; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; C112837:NCR2 protein, human; C431710:NCR3 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3