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Effects on tumor development and metastatic dissemination by the NKG2D lymphocyte receptor expressed on cancer cells

Abstract

The stimulatory NKG2D lymphocyte receptor together with its tumor-associated ligands enable the immune system to recognize and destroy cancer cells. However, with dynamic changes unfolding, cancers exploit NKG2D and its ligands for immune evasion and suppression. Recent findings have added yet another functional dimension, wherein cancer cells themselves co-opt NKG2D for their own benefit to complement the presence of its ligands for self-stimulation of parameters of tumorigenesis. Those findings are here extended to in vivo tumorigenicity testing by employing orthotopic xenotransplant breast cancer models in mice. Using human cancer lines with ectopic NKG2D expression and RNA interference (RNAi)-mediated protein depletion among other controls, we show that NKG2D self-stimulation has tumor-promoting capacity. NKG2D signals had no notable effects on cancer cell proliferation and survival but acted at the level of angiogenesis, thus promoting tumor growth, tumor cell intravasation and dissemination. NKG2D-mediated effects on tumor initiation may represent another factor in the observed overall enhancement of tumor development. Altogether, these results may have an impact on immunotherapy approaches, which currently do not account for such NKG2D effects in cancer patients and thus could be misdirected as underlying assumptions are incomplete.

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Acknowledgements

We thank Drs Steven Kelly and Sue Knoblaugh and all members of the Comparative Medicine Shared Resource laboratory for their expert veterinarian, pathology and histopathology support; Drs Julie Randolph-Habecker and Peggy Porter for their expert immunohistochemistry and histopathology advice, and all members of the Experimental Histopathology Shared Resource laboratory for their outstanding technical support. AE-G was supported by an Erwin Schrödinger Fellowship from the Austrian Science Fund (FWF; project number J3078). This study was supported by an NIH/NCI Pacific Ovarian Cancer Research Consortium (POCRC) SPORE (P50 CA083636) developmental research program grant (to VG) and NIH/NCI grant R01 CA174470 (to TS).

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Correspondence to T Spies.

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El-Gazzar, A., Cai, X., Reeves, R. et al. Effects on tumor development and metastatic dissemination by the NKG2D lymphocyte receptor expressed on cancer cells. Oncogene 33, 4932–4940 (2014). https://doi.org/10.1038/onc.2013.435

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