Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer.
In an orthotopic murine model of head and neck squamous cell carcinoma (SCC VII/SF) we studied NK cell-mediated immunity following vaccination with a recombinant vaccinia virus expressing IL-2 (rvv-IL-2). SCC VII/SF tumor cells were injected into the oral cavity of C3H/HeJ mice on day 0. Mice were vaccinated on days 7, 10, and 14 with rvv-IL-2 and control vaccines. Phenotypes, numbers, and biological activities of NK cells were determined following vaccination. Levels of expression of NK-activating receptor NKG2D and CD16 on NK cell surface were assayed in the vaccinated mice. Expression of NKG2D ligands, Rae1, and H60 on SCC VII/SF cells was also examined. Vaccination with rvv-IL-2 resulted in expansion of NK cells. NK cells isolated from rvv-IL-2-vaccinated mice had significantly higher biological activities compared with mice treated with control vaccines. NK cells from tumor-bearing mice expressed significantly lower levels of NKG2D and CD16 compared with rvv-IL-2 vaccinated mice. SCC VII/SF tumors expressed NKG2D ligand Rae 1, although H60 was not present. SCC VII/SF tumors expressed high levels of TGF-beta1, which were down-modulated by vaccination with rvv-IL-2. Incubation of NK cells with tumor homogenate or cultured supernatant of SCC VII/SF cells reduced the expression of NKG2D and CD16. This inhibition appeared to be mediated by TGF-beta1. SCC VII/SF tumors in the oral cavity of the mice secrete high quantities of TGF-beta1, which reduce the expression of NK cell receptor NKG2D as well as CD16 and inhibits biological functions of NK cells.
Dasgupta
Santanu
S
Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH 45267, USA.
Bhattacharya-Chatterjee
Malaya
M
O'Malley
Bert W
BW
Chatterjee
Sunil K
SK
D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism; D007117:Immunization, Secondary; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D018655:Lymphocyte Count; D051379:Mice; D008809:Mice, Inbred C3H; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis / Q000235:genetics; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology
C527086:Klrk1 protein, mouse; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014765:Viral Vaccines; C114735:minor H antigen H60