Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer.
The MHC class I chain-related molecules (MICs) have previously been shown to be induced on most epithelial tumor cells. Engagement of MIC by the activating immune receptor NKG2D triggers NK cells and augments antigen-specific CTL anti-tumor immunity. The MIC-NKG2D system was proposed to participate in epithelial tumor immune surveillance. Paradoxically, studies suggest that tumors may evade MIC-NKG2D-mediated immunity by MIC shedding-induced impairment of effector cell function. Here we demonstrate the first evidence to our knowledge of a significant correlation of MIC shedding and deficiency in NK cell function with the grade of disease in prostate cancer. MIC is widely expressed in prostate carcinoma. The presence of surface target MIC, however, is counteracted by shedding. A significant increase in serum levels of soluble MIC (sMIC) and deficiency in NK cell function was shown in patients with advanced cancer. Finally, the deficiency in NK cell function can be overcome by treatment with IL-2 or IL-15 in vitro. Our results suggest that (a) deficiency in MIC-NKG2D immune surveillance may contribute to prostate cancer progression, (b) sMIC may be a novel biomarker for prostate cancer, and (c) using cytokines to restore MIC-NKG2D-mediated immunity may have clinical significance for prostate cancer in cell-based adaptive immunotherapy.
Department of Medicine, University of Washington, 325 9th Avenue, Seattle, WA 98104, USA. wuj@u.washington.edu
Jennifer D
JD
Wu
Lily M
LM
Higgins
Alexander
A
Steinle
David
D
Cosman
Kathy
K
Haugk
Stephen R
SR
Plymate
D000368:Aged; D000369:Aged, 80 and over; D019002:CD56 Antigen / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D015234:HLA-A Antigens / Q000378:metabolism* / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D007157:Immunologic Surveillance; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019139:Tumor Escape
D019002:CD56 Antigen; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D019409:Interleukin-15; D007376:Interleukin-2; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D017430:Prostate-Specific Antigen