Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

Abstract

The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of "humanized" bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in "humanized" mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cellbased cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization. Introduction NK cell group 2 member D (NKG2D) and its ligands are important in antitumor immunity, as evidenced in experimental animal models. NKG2D is an activating receptor expressed by all NK cells, most NKT cells, subsets of γδ T cells, all human CD8 T cells, and activated mouse CD8 T cells (1, 2). Engagement of NKG2D can activate NK cells and costimulate CD8 and γδ T cells in vitro (3-5). Enforced expression of NKG2D ligand causes tumor cells to be rejected in syngeneic mice in a manner that is dependent on NK cells and, in some cases, primed CD8 T cells (6, 7). Neutralizing NKG2D in vivo with a specific antibody enhances host sensitivity to carcinogen-induced spontaneous tumor initiation (8). NKG2D-deficient transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are 3 times more likely to develop aggressive poorly differentiated (PD) prostate carcinoma than NKG2D WT TRAMP counterparts (9). Moreover, in NKG2D WT TRAMP mice, progression to PD prostate carcinoma was mostly associated with downregulation of NKG2D ligand expression by tumor cells (9).Curiously, most human tumors, in particular those of epithelial origins, express abundant NKG2D ligands yet progress to advanced diseases (10, 11), suggesting that NKG2D function is compromised in cancer patents. Various mechanisms have been proposed to explain how tumor cells evade NKG2D immunity. One prevailing concept is that exhaustion of NKG2D function

Immunotherapy for castration-resistant prostate cancer: Progress and new paradigms

“…For example, in advanced ovarian carcinoma, the duration of OS and PFS was significantly longer in patients with tumor-infiltrating T cells [7]. Similar data have been reported in a range of tumor types, including prostate cancer, where although the data are more limited and somewhat inconclusive, there is evidence to suggest that the infiltration of prostate tumors by certain immune cells is associated with prognosis (data are summarized in Table 1) [8][9][10][11][12][13][14]. In a joint international initiative, several national and international cancer and immunotherapy associations have initiated a protocol for developing and validating an immune score based on the type and the density of immune cells in tumor infiltrates [15].…”

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

“…Identification of additional models insensitive to pan-HER inhibitors such as AZD8931, yet sensitive to MEDI3622, should prove to be fertile grounds for these efforts in conjunction with proteomic studies to identify novel ADAM17 substrates in these models. It is noteworthy that ligands which are immunosuppressive upon shedding, such as ULBP2 (39) and MICA (40), were among the proteomics hits in the OE21 model (Table 3) and H358 lung cancer cells (Supplementary Table S3). MEDI3622-mediated inhibition of circulating levels of these ligands has the potential to restore CD8 þ T-cell and NK cell function.…”

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

“…In humans, MIC is widely expressed in prostate adenocarcinoma; however, significant serum levels of soluble MIC were observed in patients with advanced prostate cancer, indicating that prostate tumors may counteract NKG2D-mediated immunity via MIC shedding (41,42). Ligands for NKG2D (MICA/B and ULBP1) are expressed on circulating monocytes from prostate cancer patients and could be responsible for NKG2D downregulation on NK cells (43).…”