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Review
. 2013 Oct 1;2(10):e26097.
doi: 10.4161/onci.26097. Epub 2013 Oct 25.

New prospects on the NKG2D/NKG2DL system for oncology

Evelyn Ullrich  1 , Joachim Koch  2 , Adelheid Cerwenka  3 , Alexander Steinle  4
Affiliations
Review

New prospects on the NKG2D/NKG2DL system for oncology

Evelyn Ullrich et al. Oncoimmunology. .

Abstract

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.

Keywords: MIC; NK cell; NKG2D; Rae; T cell; ULBP; immune escape; tumor immunology.

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Figures

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Figure 1. Diversity of NKG2D ligands and NKG2D signaling in mice and humans. Numerous NKG2D ligands (NKG2DLs) can be expressed on the surface of mouse (left) or human (right) malignant cells. In mice, NKG2D exists as a short (NKG2D-S) or a long (NKG2D-L) splice isoform. The activation of NKG2D-S promotes the cytotoxic function of natural killer (NK) cells as well as their capacity to secrete immunostimulatory cytokines. Upon engagement of NKG2D-S, SYK or ZAP70 are recruited through the ITAM-bearing adaptor DAP12. NKG2D-L and human NKG2D signal upon the recruitment/activation of DAP10, PI3K, AKT1, and GRB2/VAV1.
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Figure 2. Upregulation of NKG2D ligands in transformed cells. Healthy cells generally do not express NKG2D ligands (NKG2DLs) and suppress the reactivity of natural killer (NK) cells by delivering inhibitory signals. In contrast, various stress conditions promote the upregulation of NKG2DLs in malignant or infected cells. ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia- and Rad3-related protein kinases; CHK-1, checkpoint kinase 1.
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