Prevalent expression of the immunostimulatory MHC class I chain–related molecule is counteracted by shedding in prostate cancer
Jennifer D. Wu, … , Kathy Haugk, Stephen R. Plymate
Jennifer D. Wu, … , Kathy Haugk, Stephen R. Plymate
Published August 16, 2004
Citation Information: J Clin Invest. 2004;114(4):560-568. https://doi.org/10.1172/JCI22206.
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Article Oncology

Prevalent expression of the immunostimulatory MHC class I chain–related molecule is counteracted by shedding in prostate cancer

Abstract

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.

Authors

Jennifer D. Wu, Lily M. Higgins, Alexander Steinle, David Cosman, Kathy Haugk, Stephen R. Plymate

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Surface NKG2D expression by NK cells from normal male donors and from pr...
Surface NKG2D expression by NK cells from normal male donors and from prostate cancer patients. Cells were isolated and stained as described in Methods. (A) Plots show surface NKG2D expression of CD3–CD56+ NK cells from a representative healthy subject and three representative prostate cancer patients (GS 7, GS 8, and GS 9). Note that NKG2Dlow and NKG2Dnormal populations were present in the patients with cancer with GS of 7 and 8. (B) Geometric mean fluorescence intensity (geo MFI) of surface NKG2D on CD3–CD56+NK cells from 10 healthy subjects, 13 prostate cancer patients with primary carcinoma with a GS of 6–7, and 10 patients with prostate cancer with a GS of 8–10. Data shown are from three independent flow cytometry measurements. Horizontal lines indicate mean value of respective groups. *P < 0.05; **P < 0.01. Note that surface NKG2D expression on CD56+ cells was measured as geo MFI, due to the heterogeneous expression of surface NKG2D. (C) Inverse correlation of surface NKG2D expression on CD3–CD56+ NK cells with serum levels of sMIC in prostate cancer patients (r = 0.57, P = 0.0049).