IntroductionThe C-type lectin-like stimulatory immune receptor NKG2D is expressed by all human NK and CD8 + T cells and by most γδ T cells (1-5). NKG2D-mediated immune activation can be triggered by interaction with its ligands (6-8): the family of stress-induced MHC class I chain-related molecules (MICs) MICA and MICB (5), and the UL16-binding protein (ULBP) family (9-11). In NK cells, the activation signal mediated by NKG2D was shown to dominate the inhibitory signal mediated by MHC class I binding to killer inhibitory receptors, leading to lysis of target cells that express NKG2D ligands (1-4). NKG2D-mediated activation signal also costimulates antigen-specific CD8 + T cell immunity and is necessary for activation of cytotoxic γδ T cells (5,(12)(13)(14)(15).According to current available data, MIC molecules are the best-characterized ligands and are the most frequently expressed ligands on epithelial tumors. MIC is induced on a broad range of epithelial tumor cells, such as melanoma, colon, breast, lung, ovary, renal, and hepatocellular carcinomas, but is absent from normal tissues (16-18). Cells expressing MIC on their surface are susceptible to NK and antigen-specific T cell immunity. Thus, surface expression of MIC on transformed cells is proposed to mark nascent tumors for immune surveillance (6-8). MIC pro-

Purpose:The type I insulin-like growth factor receptor (IGF-IR) and its ligands have been shown to play a critical role in prostate carcinoma development, growth, and metastasis. Targeting the IGF-IR may be a potential treatment for prostate cancer. A fully human monoclonal antibody, A12, specific to IGF-IR, has shown potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo. In this study, we tested the in vivo effects of A12 on androgen-dependent and androgen-independent prostate tumor growth. Experimental Design: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively.When tumor volume reached about150 to 200 mm 3 , A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks. Results: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G 1 cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G 2 -M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgenindependent LuCaP 35V tumor cells. Conclusions: Our findings suggest that A12 is a therapeutic candidate for both androgendependent and androgen-independent prostate cancer. Our findings also suggest an IGFIR^dependent activity of the androgen receptor in androgen-independent prostate cancer cells.

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.