IFN-Dependent Down-Regulation of the NKG2D Ligand H60 on Tumors

Bui, Jack D.; Carayannopoulos, Leonidas N.; Lanier, Lewis L.; Yokoyama, Wayne M.; Schreiber, Robert D.

doi:10.4049/jimmunol.176.2.905

Cited by 91 publications

(111 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, in accordance with our observations, IFN-g has been demonstrated to down-regulate the surface presentation of the murine NKG2DL H60 on methylcholanthrene-induced sarcoma. 41 The down-regulation of H60 was shown to be independent of cellular proliferation but was Besides melanoma cells, we observed a down-regulation of MICA and ULBP2 expression also for glioma cells (Fig. 3), suggesting that different tumor entities respond similar to IFN-g treatment.…”

Section: Discussionmentioning

confidence: 62%

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Schwinn

Vokhminova

Sucker

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of ab CD81 T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-c (IFN-c) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-c treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-c treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-c-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-c, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. ' 2008 Wiley-Liss, Inc.Key words: melanoma; MHC class I loss; natural killer cell; NKG2D; interferon-c Malignant melanoma is well characterized for its recognition by cytotoxic ab CD8 1 T lymphocytes (CTLs) that respond to tumorassociated peptide antigens presented in the complex with classical MHC class I surface molecules.1 Indeed, CTLs can eliminate metastatic tumors in melanoma patients, as demonstrated in different clinical trials of adoptive T cell transfer.2 The efficiency of tumor cell killing is determined by the strength of the antigen signal and co-stimulatory signals sensed by different activating receptors. Very recently, it was demonstrated that triggering of the co-stimulatory receptor NKG2D on CTLs strongly enhanced the T cells capacity to kill melanoma cells. 3Besides the importance of antigen-specific CTLs in immune surveillance of melanoma, one can assume that early detection and elimination of premalignant and malignant cutaneous melanocytes might be a major task of skin-resident innate NK cells and innate-like Vd1 gd T lymphocytes. 4 Both effectors are capable of preventing and inhibiting the growth of autologous human melanoma grafted into the skin of severe combined immunodeficient (SCID) mice.5 Interestingly, the receptor NKG2D is constitutively expressed on Vd1 gd T cells present in normal human sk...

show abstract

Section: Discussionmentioning

confidence: 62%

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Schwinn

Vokhminova

Sucker

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Immunosuppressive inflammatory-type monocytes (CD11b + IL-4Ra + ), which are present within 4T1 tumors and produce IL-13 and IFN-γ, may be responsible for some of these changes (67). Consistent with this possibility, IFN-γ has been reported to downregulate H60 on tumors, and H60 downregulation was required together with increased MHC-I expression to enhance tumor cell resistance to NK-mediated killing (68).…”

Section: Figurementioning

confidence: 93%

Suppressing T cell motility induced by anti–CTLA-4 monotherapy improves antitumor effects

Ruocco¹,

Pilones²,

Kawashima³

et al. 2012

J. Clin. Invest.

175

146

View full text Add to dashboard Cite

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8 + T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity. IntroductionThe presence of tumor-infiltrating lymphocytes (TILs) is predictive for a positive outcome in human cancer (1), but relatively little is known about how TILs interact with tumor components in vivo (2). Our understanding of this process is based on studies using mouse models and two-photon laser scanning microscopy (TPLSM) (3). Studies using the OT-1 model system with K b -OVA as an antigen in a T lymphoma context and a single study using endogenous TILs in conjunction with vaccination for a viral antigen in a lung carcinoma setting all found that stable TIL-tumor cell interactions are a feature of tumor rejection (2, 4, 5). Recent FDA approval of anti-CTLA-4-based immunotherapies for treatment of melanoma (6) has raised interest in understanding how non-antigen-specific immunotherapies influence the interactions of TILs and tumor cells. However, there are currently no data on such effects in tumors in vivo.The ability of anti-CTLA-4 mAbs to induce immune-mediated tumor regression and specific T cell memory was first demonstrated in mouse tumor models of relatively immunogenic tumors (7). Significant antitumor activity of anti-CTLA-4 mAbs against poorly immunogenic tumors required combination with additional interventions. Increased priming of antitumor T cells by vaccination and/or other "conditioning" effects of chemotherapy and radiotherapy were a prerequisite for effective anti-CTLA-4 mAb-mediated antitumor immunity in the setting of poorly immunogenic tumors (8-10).

show abstract

“…Interestingly, IFN-g and -a downregulate the expression of the NKG2D ligand H60 on MCA sarcomas (Bui et al, 2006). In addition, there is evidence that MIC-A is also downregulated by IFN-g on human melanoma cell lines (Schwinn et al, manuscript submitted).…”

Section: Nkg2d In Antitumor Responsesmentioning

confidence: 99%

NKG2D ligands in tumor immunity

2008

View full text Add to dashboard Cite

The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, cd þ and CD8 þ T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed.

show abstract

IFN-Dependent Down-Regulation of the NKG2D Ligand H60 on Tumors

Cited by 91 publications

References 49 publications

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Suppressing T cell motility induced by anti–CTLA-4 monotherapy improves antitumor effects

NKG2D ligands in tumor immunity

Contact Info

Product

Resources

About