Obstructing Shedding of the Immunostimulatory MHC Class I Chain–Related Gene B Prevents Tumor Formation

Wu, Jennifer D.; Atteridge, Catherine L.; Wang, Xuanjun; Seya, Tsukasa; Plymate, Stephen R.

doi:10.1158/1078-0432.ccr-08-1305

Cited by 51 publications

(58 citation statements)

References 39 publications

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“…The shedding of NKG2D ligands has been frequently observed in most tumors, and leads to downregulation of NKG2D on NK cells and reduced NK cell cytotoxicity. 32,44,45 It has also been found that downregulation of B7-H6 (a ligand for the activating receptor NKp30) on various tumor cell lines or release of BAG6/BTA3 (a soluble ligand for NKp30) from chronic lymphocytic leukemia cells reduces the NKp30-dependent effector functions of NK cells. 20 Suppressive cytokines (such as transforming growth factor (TGF)-b and IL-10) and regulatory T (Treg) cells within tumor microenvironments have been shown to suppress NKG2D and NKp30 expression on NK or CD8 1 T cells and also reduce MICA and ULBP expression on malignant cells.…”

Section: Nk Receptors In Tumorsmentioning

confidence: 99%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono-and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC. Keywords: activating receptor; hepatocellular carcinoma; inhibitory receptor; natural killer cell; natural killer receptor INTRODUCTION Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. 1 Common clinical risk factors for HCC include hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, heavy alcohol intake, steatohepatitis and diabetes. 2 Approximately 50% of HCC cases worldwide can be attributed to chronic HBV infection (CHB) and almost 75% of HCC cases occur in developing countries where HBV is endemic. 3,4 According to statistics, older male patients who are infected with HBV genotype C or co-infected with HCV, have high levels of viral load and have been exposed to the aflatoxin, or older male patients who have a family history of HCC tend to have a high risk of developing HCC. [5][6][7] Accumulating clinical and epidemiological evidence shows a significant correlation between chronic HBV infection and hepatocarcinogenesis. However, the underlying mechanisms

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Section: Nk Receptors In Tumorsmentioning

confidence: 99%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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“…No homolog of human MIC has yet been described in mice. In general, human or mouse NKG2D does not recognize the ligands of their counterparts, except that mouse NKG2D can recognize human MICB and selective alleles of human MICA (32)(33)(34). Most importantly, tumor shedding of NKG2D ligands to downregulate NKG2D function has been described and proposed as one of the immune evasion mechanisms in human cancer, but has not been described in mice.…”

Section: Introductionmentioning

confidence: 99%

“…To clarify the impact of human NKG2D ligands on cancer, we exploited the knowledge that the human NKG2D ligand MICB can stimulate mouse NKG2D immunity (33,34) and generated 2 unique lines of "humanized" bi-transgenic (bi-Tg) mouse models, TRAMP/MICB and TRAMP/MICB.A2. The former expresses the native human MICB, which can be shed by tumor cells, while the latter expresses an engineered membrane-restricted MICB (designated as MICB.A2) in the prostate of the autochthonous TRAMP mouse (33,35,36). Using these models, for what we believe is the first time, we conclusively demonstrate the distinct roles of membrane-bound NKG2D ligands and tumor-derived soluble NKG2D ligands on cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

et al. 2013

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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

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“…Apart from reducing NKG2D-L expression on the tumor cell surface, the release of soluble molecules may also impair immune surveillance by promoting down-regulation of NKG2D (12,13). In fact, the sustained presence in vivo of NKG2D-L down-modulates the receptor (14,15), and, at least in mouse models, blocking shedding of NKG2D-L can prevent tumor formation (16). In patients with colorectal or prostate cancer, hepatocellular carcinoma, and neuroblastoma, decreased NKG2D expression and impaired activation of NK cells was associated with high levels of soluble MICA in serum (17)(18)(19)(20).…”

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confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

141

166

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Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.NKG2D is an activating immune receptor that can be expressed by most cytotoxic lymphocytes, including NK and CD8ϩ T cells (1). Engagement of NKG2D by its ligands leads to the activation or co-stimulation of lysis and cytokine secretion (for review, see Ref. 2). In humans, NKG2D ligands (NKG2D-L) 5 occur in two families of proteins: the polymorphic family of MHC-I-related chain A/B (MICA/B) and the multigene family of UL16-binding proteins (ULBPs, also known as RAET1A-E). In total, 10 members of this gene family have been described, of which six can be expressed as functional proteins (3). Two members of the ULBP family have a transmembrane region (ULBP4 and -5), like MICA/B, whereas the other ULBP molecules are linked to the cell membrane via glycosylphosphatidylinositol (GPI) anchors. The existence of such a large number of ligands for a single receptor is not fully understood but may reflect a differential role for different ligands in immune surveillance or an evolutionary response to selective pressures exerted by pathogens or cancer.In general, NKG2D-L are not expressed ubiquitously; instead, they are expressed in response to several types of cellular stress, such as pathogen infection (4), DNA damage (5), proteasome inhibition (6), and tumor transformation (7). For example, MICA/B are expressed in epithelial tumors, melanoma, neuroblastoma, various hematopoietic malignancies, and carcinomas; ULBPs are found in leukemia, gliomas and melanomas. An additional complication is that mRNA can be found in many cells that do not express protein suggesting post-transcriptional regulation of NKG2D-L expression (8 -10).Mice deficient in NKG2D expression show an enhanced susceptibility to the development of tumors (11). However, shedding NKG2D-L as soluble molecules allows tumor cells to evade NKG2D surveillance. Apart from reducing NKG2D-L expression on the tumor cell surface, the release of soluble molecules may also impair immune surveillance by promoting down-regulation of NKG2D (12, 13). In fact, the sustained presence in vivo of NKG2D-L down-modulates...

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Obstructing Shedding of the Immunostimulatory MHC Class I Chain–Related Gene B Prevents Tumor Formation

Cited by 51 publications

References 39 publications

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

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