NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy

Guerra, Nadia; Tan, Ying Xim; Joncker, Nathalie T.; Choy, Augustine; Gallardo, Fermin; Xiong, Na; Knoblaugh, Susan; Cado, Dragana; Greenberg, Norman M.; Raulet, David H.

doi:10.1016/j.immuni.2008.04.001

Cited by 170 publications

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“…Although NKG2D deficiency entailed accelerated tumor growth in both models, selection against NKG2D-L expression was identified as a tumor escape mechanism only in the prostate carcinoma but not in the lymphoma model. This discrepancy in the latter study was explained by other mechanisms circumventing activity of NKG2D 1 effector cells during lymphoma development [19]. The question what is the nature of the NKG2D-L involved was not addressed in our study and has to be elucidated in future work.…”

Section: Discussionmentioning

confidence: 67%

“…Direct evidence for NKG2D-dependent tumor surveillance was recently provided by using transgenic mice that developed spontaneous malignancies of the prostate or the lymphoid system [19]. Although NKG2D deficiency entailed accelerated tumor growth in both models, selection against NKG2D-L expression was identified as a tumor escape mechanism only in the prostate carcinoma but not in the lymphoma model.…”

Section: Discussionmentioning

confidence: 99%

“…However, a possible role of other ligands could not be excluded in these studies. Direct evidence for a role of NKG2D receptors in tumor surveillance was provided by a recent study where onset of spontaneous malignancies was accelerated when mice were devoid of NKG2D expression [19].…”

Section: Introductionmentioning

confidence: 99%

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Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c‐myc‐transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D‐L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK‐cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re‐expressed MHC class I and lost NKG2D‐L, suggesting a role of these two signals for NK cell‐mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D‐L levels suggested that NK cell‐dependent tumor control required a priming and a triggering signal that were provided by MHC class I down‐regulation and by NKG2D‐L, respectively. Deleting either of the “two signals” resulted in tumor escape. At early disease stages, immune stimulation through TLR‐ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell‐dependent manner. Thus, NK‐receptor coengagement is crucial for NK‐cell functions in vivo and especially for NK cell‐mediated tumor surveillance.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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“…Ectopic expression of NKG2D ligand leads to anticancer immune responses to transplanted tumours in mice, and the NKG2D knockout mouse has an increased susceptibility to certain types of cancer [18][19][20]. The importance of NKG2D in antiviral immune responses is illustrated by the fact that many viruses have evolved one, and sometimes multiple, mechanisms to prevent cell-surface expression of NKG2D ligand [21].…”

Section: Introductionmentioning

confidence: 99%

ULBP6/RAET1L is an additional human NKG2D ligand

Eagle¹,

Traherne²,

Hair³

et al. 2009

Eur J Immunol

107

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To date five ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) genes, encoded on human chromosome 6q24.2-q25.3, have been shown to encode ligands of the activating immunoreceptor NKG2D. Here, we show that a sixth gene, ULBP6/RAET1L, is a polymorphic locus that expresses a functional transcript. ULBP6 had a more restricted expression profile in cell lines and primary human tissues than other NKG2D ligands, but expression was detected in several human papillomavirus-positive cervical carcinoma cell lines and was inducible on infection with human CMV. ULBP6 bound to recombinant NKG2D as well as the human CMV immune evasion molecule UL16. By confocal microscopy we show that UL16 retains ULBP6 inside the cell, preventing it from reaching the cell surface. Expression of ULBP6 on target cells induced a significant increase in NK-cell killing. Comparison of ULBP6 with ULBP4 and ULBP5 indicated that differences in recombinant NKG2D binding correlated with differences in NK-cell activation.Key words: Immune evasion . Infectious diseases . Innate immunity . NK cells . NK-cell ligandsSupporting Information available online IntroductionThe stimulatory immune receptor NKG2D (NK group 2, member D) plays an important role in anti-pathogen and anti-cancer immune responses [1]. In humans, NKG2D is expressed by all NK cells and almost all abT cells and gdT cells [1]. It is normally absent from CD4 1 T cells but can be induced in some circumstances, such as in rheumatoid arthritis patients [2] and on exposure to human CMV (HCMV) [3]. NKG2D signalling function is mediated exclusively through the adaptor molecule DAP10 in humans [4], whereas mouse NKG2D can associate with both DAP10 and DAP12 [5,6]. The downstream effects of NKG2D ligation are now recognised to depend on synergy with other cell surface receptors and cytokines, with IL-15 signalling recently being shown to have a particularly close association with the NKG2D-DAP10 complex [7,8].NKG2D ligands are a diverse array of cellular proteins, all of which have structural similarity to MHC class I molecules [9]. In humans NKG2D ligands are encoded in two gene families, MIC (MHC-class-I-polypeptide related sequence) and ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) [10][11][12][13]. We will follow the ULBP nomenclature from this point. In mouse, NKG2D ligands comprise three members of the H60 family, five members of the Rae1 (retinoic acid early inducible transcript-1) family, and Mult-1 (murine ULBP-like transcript) [14][15][16][17].According to the initial models of NKG2D function, its ligands were thought to be largely absent from healthy cells, but their expression could be induced on viral infection and on tumourigenesis [1]. Ectopic expression of NKG2D ligand leads to anticancer immune responses to transplanted tumours in mice, and the NKG2D knockout mouse has an increased susceptibility to certain types of cancer [18][19][20]. The importance of NKG2D in antiviral immune responses is illustrated by the fact that ...

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“…DNAM-1-and NKG2D-mediated anti-tumor responses can be further enhanced by treatment with IL-2 or/and IL-12, respectively [27,28]. Importantly, it was reported recently that the NKG2D receptor was essential for effective immunosurveillance of lymphoma and prostate carcinoma in mouse models of spontaneously arising malignancies [29].…”

Section: Introductionmentioning

confidence: 99%

Shaping of NK Cell Responses by the Tumor Microenvironment

Stojanović

Correia

Cerwenka

2012

Cancer Microenvironment

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Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokineproducing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.

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NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy

Cited by 170 publications

References 0 publications

Requirements for control of B‐cell lymphoma by NK cells

Requirements for control of B‐cell lymphoma by NK cells

ULBP6/RAET1L is an additional human NKG2D ligand

Shaping of NK Cell Responses by the Tumor Microenvironment

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