Research ArticleImmunotherapy

Immunological Visibility: Posttranscriptional Regulation of Human NKG2D Ligands by the EGF Receptor Pathway

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Science Translational Medicine  09 Apr 2014:
Vol. 6, Issue 231, pp. 231ra49
DOI: 10.1126/scitranslmed.3007579

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Attracting Big Brother

It is increasingly acknowledged that immune cells serve as the surveillance system of the body—constantly on the lookout for things that are out of place, such as infections or cancer. Indeed, researchers and clinicians are now trying to harness the immune system either by overcoming inhibitions or by pointing them at particular targets. But what happens when the target tries to hide? Vantourout et al. now look at the mechanisms that regulate immunological visibility.

The authors stressed human epithelial cells by various means and found that up-regulation of ligands that activate NKG2D, a lymphocyte-activating receptor, was dependent on epithelial growth factor receptor (EGFR). They looked further into the mechanism and discovered that EGFR activation resulted in relocalization of AUF1 proteins, which normally destabilize NKG2D ligands, and resulted in increased expression of these ligands—and improved immunological visibility. What’s more, EGFR activation is one of the most common forms of dysregulation underpinning human carcinomas, and primary tumors with high EGFR expression showed higher NKG2D ligand expression levels. Conversely, NKG2D ligand expression was reduced by erlotinib and cetuximab, two EGFR inhibitors commonly used in the clinic. These data suggest that the effects of therapeutics that limit cancer growth should be considered with immunotherapy.