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Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma
Journal article   Peer reviewed

Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma

Ekaterina S Doubrovina, Mikhail M Doubrovin, Elena Vider, Richard B Sisson, Richard J O'Reilly, Bo Dupont and Yatin M Vyas
The Journal of immunology (1950), Vol.171(12), pp.6891-6899
12/15/2003
DOI: 10.4049/jimmunol.171.12.6891
PMID: 14662896

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Abstract

Evasion of host immune responses is well documented for viruses and may also occur during tumor immunosurveillance. The mechanisms involve alterations in MHC class I expression, Ag processing and presentation, chemokine and cytokine production, and lymphocyte receptor expression. Epithelial tumors overexpress MHC class I chain-related (MIC) molecules, which are ligands for the activating receptor NKG2D on NK and T cells. We report that NK cells from patients with colorectal cancer lack expression of activating NKG2D and chemokine CXCR1 receptors, both of which are internalized. Serum levels of soluble MIC (sMIC) are elevated and are responsible for down-modulation of NKG2D and CXCR1. In contrast, high serum levels of CXC ligands, IL-8, and epithelial-neutrophil-activating peptide (ENA-78) do not down-modulate CXCR1. In vitro, internalization of NKG2D and CXCR1 occurs within 4 and 24 h, respectively, of incubating normal NK cells with sMIC-containing serum. Furthermore, natural cytotoxicity receptor NKp44 and chemokine receptor CCR7 are also down-modulated in IL-2-activated NK cells cocultured in MIC-containing serum-an effect secondary to the down-modulation of NKG2D and not directly caused by physical association with sMIC. The patients' NK cells up-regulate expression of NKG2D, NKp44, CXCR1, and CCR7 when cultured in normal serum or anti-MIC Ab-treated autologous serum. NKG2D(+) but not NKG2D(-) NK cells are tumoricidal in vitro, and in vivo they selectively traffic to the xenografted carcinoma, form immunological synapse with tumor cells, and significantly retard tumor growth in the SCID mice. These results suggest that circulating sMIC in the cancer patients deactivates NK immunity by down-modulating important activating and chemokine receptors.
 Neoplasm Transplantation Receptors, Interleukin-8A - biosynthesis Adenocarcinoma - pathology Receptors, Interleukin-8A - antagonists & inhibitors Coculture Techniques Humans Neoplasm Proteins - physiology Transplantation, Heterologous Neoplasm Proteins - metabolism Colonic Neoplasms - metabolism Receptors, Immunologic - antagonists & inhibitors Histocompatibility Antigens Class I - metabolism Adenocarcinoma - metabolism Receptors, Immunologic - biosynthesis Colonic Neoplasms - immunology Receptors, Natural Killer Cell Receptors, Chemokine - biosynthesis Killer Cells, Natural - immunology Growth Inhibitors - biosynthesis Histocompatibility Antigens Class I - biosynthesis Receptors, Chemokine - antagonists & inhibitors Tumor Cells, Cultured Tumor Escape - immunology Killer Cells, Natural - transplantation NK Cell Lectin-Like Receptor Subfamily K Neoplasm Proteins - biosynthesis Adenocarcinoma - immunology Receptors, CCR7 Histocompatibility Antigens Class I - physiology Solubility Mice, SCID Animals Down-Regulation - immunology Colonic Neoplasms - pathology Ligands Mice Killer Cells, Natural - metabolism Cytotoxicity, Immunologic - immunology Immunity, Cellular Cell Line, Transformed Growth Inhibitors - antagonists & inhibitors

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