Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma Journal Article
| Authors: | Doubrovina, E. S.; Doubrovin, M. M.; Vider, E.; Sisson, R. B.; O'Reilly, R. J.; Dupont, B.; Vyas, Y. M. |
| Article Title: | Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma |
| 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. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; adenocarcinoma; antigen expression; t lymphocyte; animal cell; mouse; animal; metabolism; mouse mutant; animals; mice; interleukin 8; neoplasm proteins; cell line; animal experiment; animal model; protein; colonic neoplasms; down-regulation; antineoplastic activity; cytotoxicity; in vitro study; pathology; mice, scid; tumor cells, cultured; transplantation; physiology; cytokine; antigen presentation; biosynthesis; immunology; cellular immunity; immune response; chemokine; xenograft; cell culture; colon tumor; tumor protein; hla antigen class 1; histocompatibility antigens class i; ligand; transplantation, heterologous; cell line, transformed; ligands; natural killer cell; killer cells, natural; cytokine production; cytotoxicity, immunologic; down regulation; upregulation; neoplasm transplantation; immunosurveillance; major histocompatibility complex; chemokine receptor ccr7; virus; colon adenocarcinoma; scid mouse; chemokine receptor; receptors, chemokine; internalization; receptors, immunologic; major histocompatibility antigen class 1; natural killer cell receptor nkg2d; cancer transplantation; solubility; coculture; coculture techniques; immunity, cellular; growth inhibitor; growth inhibitors; immunoglobulin receptor; lymphocyte receptor; tumor escape; alpha chemokine; epithelial derived neutrophil activating factor 78; humans; human; priority journal; article; protein p44; cc chemokine receptor 7; chemokine receptor cxcr1; mica protein; micb antigen; nkg2 protein; protein nkp44; receptors, interleukin-8a |
| Journal Title: | Journal of Immunology |
| Volume: | 171 |
| Issue: | 12 |
| ISSN: | 0022-1767 |
| Publisher: | The American Association of Immunologists, Inc |
| Date Published: | 2003-12-15 |
| Start Page: | 6891 |
| End Page: | 6899 |
| Language: | English |
| PUBMED: | 14662896 |
| PROVIDER: | scopus |
| DOI: | 10.4049/jimmunol.171.12.6891 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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