Abstract
EGFR activation increases NKG2D ligand expression in cancer cell lines and primary keratinocytes.
Major finding: EGFR activation increases NKG2D ligand expression in cancer cell lines and primary keratinocytes.
Mechanism: EGFR signaling blocks AUF-mediated NKG2D ligand mRNA destabilization to promote expression.
Impact: Reducing EGFR signaling may impede cancer recognition and responses by NK and T cells.
Activation of the natural killer (NK) group 2, member D (NKG2D) receptor on NK and T cells by stress ligands can promote recognition of tumor cells. NKG2D and its multitude of ligands thus constitute an important axis in immune surveillance, and their expression may determine whether cancer cells evade immune recognition. Vantourout and colleagues sought to understand how NKG2D ligand expression is regulated in human epithelial cells and found that protein and mRNA levels of the NKG2D ligand MHC class I-related chain A (MICA) and of other ligands were significantly increased following exposure to ultraviolet B (UVB) radiation but not by other DNA damaging agents. UVB-induced MICA upregulation depended on EGF signaling, which made the cells targets for cytolytic NK and γδ T cells in an NKG2D-dependent manner. Mechanistically, EGF stabilized NKG2D ligand mRNAs in a MAPK-dependent manner by promoting nuclear exclusion of AU-rich element RNA-binding protein 1 (AUF1), which normally destabilizes mRNAs by binding to AU-rich elements that are found in the mRNAs encoding MICA and other human NKG2D ligands. In human breast cancers, NKG2D ligand expression strikingly correlated with EGFR expression and negatively correlated with a negative regulator of EGF signaling, suggesting that these findings may be clinically relevant. In that regard, EGF-induced cell surface expression of NKG2D ligands was reduced by the clinically used EGFR inhibitors erlotinib and cetuximab. This finding provokes the concern that such widely used inhibitors may promote evasion of immune surveillance by downregulating NKG2D ligand expression and that this impairment of immune surveillance might underlie the frequent skin toxicities and irritations that often affect patient compliance. The identification of EGFR as a mediator of NKG2D-dependent immunogenicity strongly suggests that the efficacy of EGFR inhibitors might be improved by adjuvants that simultaneously enhance immune responses.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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