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Alexander Steinle - One of the best experts on this subject based on the ideXlab platform.
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Arming cytotoxic lymphocytes for cancer immunotherapy by means of the NKG2D/NKG2D-ligand system.
Expert opinion on biological therapy, 2020Co-Authors: Mariya Lazarova, Winfried S. Wels, Alexander SteinleAbstract:The activating NKG2D receptor plays a central role in the immune recognition and elimination of abnormal self-cells by cytotoxic lymphocytes. NKG2D binding to cell stress-inducible ligands (NKG2DL)...
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Impairment of NKG2D-Mediated Tumor Immunity by TGF-β.
Frontiers in immunology, 2019Co-Authors: Mariya Lazarova, Alexander SteinleAbstract:Transforming growth factor-β (TGF-β) suppresses innate and adaptive immune responses via multiple mechanisms. TGF-β also importantly contributes to the formation of an immunosuppressive tumor microenvironment thereby promoting tumor growth. Amongst others, TGF-β impairs tumor recognition by cytotoxic lymphocytes via NKG2D. NKG2D is a homodimeric C-type lectin-like receptor expressed on virtually all human NK cells and cytotoxic T cells, and stimulates their effector functions upon engagement by NKG2D ligands (NKG2DL). While NKG2DL are mostly absent from healthy cells, their expression is induced by cellular stress and malignant transformation, and, accordingly, frequently detected on various tumor cells. Hence, the NKG2D axis is thought to play a decisive role in cancer immunosurveillance and, obviously, often is compromised in clinically apparent tumors. There is mounting evidence that TGF-β, produced by tumor cells and immune cells in the tumor microenvironment, plays a key role in blunting the NKG2D-mediated tumor surveillance. Here, we review the current knowledge on the impairment of NKG2D-mediated cancer immunity through TGF-β and discuss therapeutic approaches aiming at counteracting this major immune escape pathway. By reducing tumor-associated expression of NKG2DL and blinding cytotoxic lymphocytes through down-regulation of NKG2D, TGF-β is acting upon both sides of the NKG2D axis severely compromising NKG2D-mediated tumor rejection. Consequently, novel therapies targeting the TGF-β pathway are expected to reinvigorate NKG2D-mediated tumor elimination and thereby to improve the survival of cancer patients.
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Cutting an NKG2D Ligand Short: Cellular Processing of the Peculiar Human NKG2D Ligand ULBP4
Frontiers Media S.A., 2018Co-Authors: Tobias Zöller, Mareike Wittenbrink, Meike Hoffmeister, Alexander SteinleAbstract:Stress-induced cell surface expression of MHC class I-related glycoproteins of the MIC and ULBP families allows for immune recognition of dangerous “self cells” by human cytotoxic lymphocytes via the NKG2D receptor. With two MIC molecules (MICA and MICB) and six ULBP molecules (ULBP1–6), there are a total of eight human NKG2D ligands (NKG2DL). Since the discovery of the NKG2D–NKG2DL system, the cause for both redundancy and diversity of NKG2DL has been a major and ongoing matter of debate. NKG2DL diversity has been attributed, among others, to the selective pressure by viral immunoevasins, to diverse regulation of expression, to differential tissue expression as well as to variations in receptor interactions. Here, we critically review the current state of knowledge on the poorly studied human NKG2DL ULBP4. Summarizing available facts and previous studies, we picture ULBP4 as a peculiar ULBP family member distinct from other ULBP family members by various aspects. In addition, we provide novel experimental evidence suggesting that cellular processing gives rise to mature ULBP4 glycoproteins different to previous reports. Finally, we report on the proteolytic release of soluble ULBP4 and discuss these results in the light of known mechanisms for generation of soluble NKG2DL
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New prospects on the NKG2D/NKG2DL system for oncology.
Oncoimmunology, 2013Co-Authors: Evelyn Ullrich, Joachim Koch, Adelheid Cerwenka, Alexander SteinleAbstract:The activating immunoreceptor NKG2D endows cytotoxic lymphocytes with the capacity to recognize and eliminate infected or malignant cells. The recognition of such harmful cells is enabled by binding of NKG2D to various MHC class I-related glycoproteins, which are upregulated in the course of viral infection or malignant transformation. The past years have witnessed substantial progress in our understanding of the mechanisms underlying the regulation of NKG2D ligands (NKG2DLs) by malignant cells, of tumor-associated countermeasures promoting escape from NKG2D-dependent immunosurveillance, and of therapeutic measures that may bolster the NKG2D/NKG2DL system against malignancies. Here, we summarize the current knowledge on the NKG2D/NKG2DL system and outline opportunities to exploit the tumoricidal function of NKG2D for anticancer immunotherapy.
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Comprehensive Analysis of NKG2D Ligand Expression and Release in Leukemia: Implications for NKG2D-Mediated NK Cell Responses
Journal of immunology (Baltimore Md. : 1950), 2012Co-Authors: Julia Hilpert, Alexander Steinle, Ludger Grosse-hovest, Frank Grünebach, Corina Buechele, Tina Nuebling, Tobias Raum, Helmut R. SalihAbstract:Ligands of the prototypical activating NK receptor NKG2D render cancer cells susceptible to NK cell-mediated cytolysis if expressed at sufficiently high levels. However, malignant cells employ mechanisms to evade NKG2D-mediated immunosurveillance, such as NKG2D ligand (NKG2DL) shedding resulting in reduced surface expression levels. In addition, systemic downregulation of NKG2D on NK cells of cancer patients has been observed in many studies and was attributed to soluble NKG2DL (sNKG2DL), although there also are conflicting data. Likewise, relevant expression of NKG2DL in leukemia has been reported by some, but not all studies. Hence, we comprehensively studied expression, release, and function of the NKG2D ligands MHC class I chain-related molecules A and B and UL16-binding proteins 1-3 in 205 leukemia patients. Leukemia cells of most patients (75%) expressed at least one NKG2DL at the surface, and all investigated patient sera contained elevated sNKG2DL levels. Besides correlating NKG2DL levels with clinical data and outcome, we demonstrate that sNKG2DL in patient sera reduce NKG2D expression on NK cells, resulting in impaired antileukemia reactivity, which also critically depends on number and levels of surface-expressed NKG2DL. Together, we provide comprehensive data on the relevance of NKG2D/NKG2DL expression, release, and function for NK reactivity in leukemia, which exemplifies the mechanisms underlying NKG2D-mediated tumor immunosurveillance and escape.
David H Raulet - One of the best experts on this subject based on the ideXlab platform.
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rae1 ligands for the NKG2D receptor are regulated by sting dependent dna sensor pathways in lymphoma
Cancer Research, 2014Co-Authors: Adeline R Lam, Nina Le Bert, Yu J Shen, Li F M Tang, Gordon Minru Xiong, John Ludovic Croxford, Christine Xinger Koo, Ken J Ishii, Shizuo Akira, David H RauletAbstract:The immunoreceptor NKG2D originally identified in natural killer (NK) cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DL) is induced by the DNA damage response (DDR), which is often activated constitutively in cancer cells, revealing them to NK cells as a mechanism of immunosurveillance. Here, we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines that express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3(+/-);Eμ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared with Irf3(+/+);Eμ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.
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mouse cd94 nkg2a is a natural killer cell receptor for the nonclassical major histocompatibility complex mhc class i molecule qa 1b
Journal of Experimental Medicine, 1998Co-Authors: Russell E Vance, Jennifer R Kraft, John D Altman, Peter E Jensen, David H RauletAbstract:Natural killer (NK) cells preferentially lyse targets that express reduced levels of major histocompatibility complex (MHC) class I proteins. To date, the only known mouse NK receptors for MHC class I belong to the Ly49 family of C-type lectin homodimers. Here, we report the cloning of mouse NKG2A, and demonstrate it forms an additional and distinct class I receptor, a CD94/NKG2A heterodimer. Using soluble tetramers of the nonclassical class I molecule Qa-1b, we provide direct evidence that CD94/NKG2A recognizes Qa-1b. We further demonstrate that NK recognition of Qa-1b results in the inhibition of target cell lysis. Inhibition appears to depend on the presence of Qdm, a Qa-1b-binding peptide derived from the signal sequences of some classical class I molecules. Mouse NKG2A maps adjacent to CD94 in the heart of the NK complex on mouse chromosome six, one of a small cluster of NKG2-like genes. Our findings suggest that mouse NK cells, like their human counterparts, use multiple mechanisms to survey class I expression on target cells.
Kiyoshi Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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abstract 3806 the pattern of NKG2Dl expressions determines immunogenicity and antitumor effect of protein bound polysaccharide k in tumor bearing mouse models
Cancer Research, 2018Co-Authors: Tomohiro Takehara, Kenzo Soejima, Tomoko Betsuyaku, Kiyoshi YoshimuraAbstract:Background and Aim: Natural killer group 2, member D ligands (NKG2DLs) have paradoxical immunological characteristics, exerting both immune-stimulatory and immune-suppressive effects on T cell activation. First, we attempted to determine the relationship between the antitumor effect of protein-bound polysaccharide-K (PSK) in a tumor-bearing mouse model and the expression profile of NKG2DLs on a tumor. Next, we investigated whether NKG2DL expression on tumor cells affects T cell activation by examining the expression of NKG2D on and IFN-γ production in CD8+ T cells in mice bearing NKG2DL–expressing and NKG2DL–nonexpressing tumors.Materials and Methods: PSK was administered to evaluate its effectiveness against tumor growth. The expression of Rae-1 and H60 were analyzed in the cell lines. Results: PSK showed the highest antitumor effects in mice implanted with cells expressing neither Rae-1 nor H60. PSK had little antitumor effect in mice implanted with cells expressing both Rae-1 and H60. A correlation between the expression of NKG2DLs and the antitumor effect of PSK was observed. After PSK administration, INF-γ production in CD8+ T cells increased in mice with cells expressing neither Rae-1 nor H60, but did not change in mice implanted with cells expressing both Rae-1 and H60.Conclusion: we demonstrated that the expression pattern of NKG2DLs affects tumor immunity and the efficacy of immunotherapy in a tumor-bearing mouse model. In particular, the expression of H60 and Rae-1 family members may be an immunosuppressive factor. Further analysis is required to gain a better understanding of the mechanism of interaction between NKG2D expressed on immune effector cells and H60/Rae-1 expression on tumors. Although NKG2DL expression may represent a marker predicting response to immunotherapy, further studies in humans are required to validate this finding in the clinical setting. Citation Format: Tomohiro Takehara, Kenzo Soejima, Tomoko Betsuyaku, Kiyoshi Yoshimura. The pattern of NKG2DL expressions determines immunogenicity and antitumor effect of protein-bound polysaccharide-K in tumor-bearing mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3806.
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Chimeric antigen receptor T cell therapy targeting NKG2D ligand.
Journal of Clinical Oncology, 2016Co-Authors: Tetsuhiko Asao, Moeko Inoue, Rie Ishibashi, Masafumi Fuse, Yoshie Miura, Hidenobu Ishizaki, Kiyoshi YoshimuraAbstract:e14523Background: Chimeric antigen receptor T cell (CAR-T) therapy is promising immunotherapy for cancer. While CAR-T therapy has shown encouraging results against CD19 in acute lymphoblastic lymphoma and other hematologic malignancies, CAR-T therapy targeting solid tumors is having problem with shortage of appropriate target antigens. NKG2D ligand (NKG2DL) is a ligand of NKG2D, which is expressed mainly on NK and γδ T cells, could be an attractive target of CAR-T therapy. NKG2DL such as MICA, MICB, and ULBP1 (UL16 binding protein 1) to ULBP3 are reported to be expressed on several kinds of tumors. Expression of MICA/MICB on tumor cells are reported to correlate with poor prognosis. Here we demonstrate that co-expressions of ULBP1 in cancer and NKG2D in peripheral blood mononuclear cells are associated with better prognosis in gastric cancer. For further analysis, we are investigating whether NKG2DL is appropriate target and which one among NKG2DL is able to be a target for the CAR-T therapy. Methods: We ...
Annette Paschen - One of the best experts on this subject based on the ideXlab platform.
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tumor suppressive micrornas mir 34a c control cancer cell expression of ulbp2 a stress induced ligand of the natural killer cell receptor NKG2D
Cancer Research, 2012Co-Authors: Anja Heinemann, Alexander Steinle, Fang Zhao, Sonali Pechlivanis, Jurgen Eberle, Sven Diederichs, Dirk Schadendorf, Annette PaschenAbstract:Malignant cells express ligands for the natural killer cell immunoreceptor NKG2D, which sensitizes to early recognition and elimination by cytotoxic lymphocytes and provides an innate barrier against tumor development. However, the mechanisms that control NKG2D ligand (NKG2DL) expression in tumor cells remain unknown. We recently identified the NKG2DL ULBP2 as strong prognostic marker in human malignant melanoma. Here, we provide evidence that the tumor-suppressive microRNAs (miRNA) miR-34a and miR-34c control ULBP2 expression. Reporter gene analyses revealed that both miRNAs directly targeted the 3′-untranslated region of ULBP2 mRNA and that levels of miR-34a inversely correlated with expression of ULBP2 surface molecules. Accordingly, treatment of cancer cells with miRNA inhibitors led to upregulation of ULBP2, whereas miR-34 mimics led to downregulation of ULBP2, diminishing tumor cell recognition by NK cells. Treatment with the small molecule inhibitor Nutlin-3a also decreased ULBP2 levels in a p53-dependent manner, which was due to a p53-mediated increase in cellular miR-34 levels. Taken together, our study shows that tumor-suppressive miR-34a and miR-34c act as ULBP2 repressors. These findings also implicate p53 in ULBP2 regulation, emphasizing the role of the specific NKG2DL in tumor immune surveillance. Cancer Res; 72(2); 1–12. ©2011 AACR .
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differential clinical significance of individual NKG2D ligands in melanoma soluble ulbp2 as an indicator of poor prognosis superior to s100b
Clinical Cancer Research, 2009Co-Authors: Annette Paschen, Antje Sucker, Bettina Hill, Iris Moll, Marc Zapatka, Xuan Duc Nguyen, Geok Choo Sim, Isabelle Gutmann, Jessica C Hassel, Jurgen C BeckerAbstract:Purpose: Cytotoxic lymphocytes interact with human tumor cells via the activating immunoreceptor NKG2D, recognizing a variety of stress-associated MIC and ULBP surface molecules. However, tumors can escape from this immunosurveillance by shedding NKG2D ligands (NKG2DL), rendering the soluble products detectable in patients9 sera. Experimental Design: To elucidate the clinical significance of NKG2DL diversity, we studied their expression on melanoma tissues and their presence as soluble molecules in sera from >200 melanoma patients and compared the latter with the well-established serum marker S100B. Results: Immunohistochemistry revealed a heterogeneous expression of MIC and ULBP2 molecules between and within melanoma metastases. Compared with MIC, ULBP2 was less frequently expressed. Accordingly, elevated levels of soluble ULBP2 (sULBP2) were detected in sera of melanoma patients less frequently than elevated levels of soluble MICA (sMICA), although both soluble NKG2DL (sNKG2DL) were significantly increased compared with sera of healthy controls ( P P P = 0.0003). Elevated serum levels of either sNKG2DL correlated with reduced overall survival, albeit considerably stronger for sULBP2 ( P P = 0.011). In early-stage (I-III) melanoma patients, only sULBP2 ( P P = 0.0015) and S100B ( P = 0.013) but not sMICA as independent predictors of prognosis. Conclusion: Our data reveal marked differences in the clinical significance of individual sNKG2DL. Only sULBP2 is an independent predictor of prognosis, the significance of which is superior to the well-established and widely used melanoma serum marker S100B. (Clin Cancer Res 2009;15(16):5208–15)
Jun Tang - One of the best experts on this subject based on the ideXlab platform.
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NKG2D+CD4+ T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand- Dependent Manner in Systemic Lupus Erythematosus.
Scientific reports, 2017Co-Authors: Di Yang, Zhiqiang Tian, Mengjie Zhang, Weibing Yang, Jun TangAbstract:Systemic lupus erythematosus (SLE) features a decreased pool of CD4+CD25+Foxp3+ T regulatory (Treg) cells. We had previously observed NKG2D+CD4+ T cell expansion in contrast to a decreased pool of Treg cells in SLE patients, but whether NKG2D+CD4+ T cells contribute to the decreased Treg cells remains unclear. In the present study, we found that the NKG2D+CD4+ T cells efficiently killed NKG2D ligand (NKG2DL)+ Treg cells in vitro, whereby the surviving Treg cells in SLE patients showed no detectable expression of NKG2DLs. It was further found that MRL/lpr lupus mice have significantly increased percentage of NKG2D+CD4+ T cells and obvious decreased percentage of Treg cells, as compared with wild-type mice. Adoptively transferred NKG2DL+ Treg cells were found to be efficiently killed in MRL/lpr lupus mice, with NKG2D neutralization remarkably attenuating this killing. Anti-NKG2D or anti-interferon-alpha receptor (IFNAR) antibodies treatment in MRL/lpr mice restored Treg cells numbers and markedly ameliorated the lupus disease. These results suggest that NKG2D+CD4+ T cells are involved in the pathogenesis of SLE by killing Treg cells in a NKG2D-NKG2DL-dependent manner. Targeting the NKG2D-NKG2DL interaction might be a potential therapeutic strategy by which Treg cells can be protected from cytolysis in SLE patients.
