Editors' ChoiceCancer Immunology

Sabotaging Immunosurveillance

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Sci. Signal.  22 Apr 2014:
Vol. 7, Issue 322, pp. ec105
DOI: 10.1126/scisignal.2005395

Immune cells can limit tumor growth by recognizing and destroying cancer cells. Natural killer (NK) cells and cytolytic T cells are activated through the receptor NKG2D (NK group 2, member D) by major histocompatibility complex (MHC) class I–related chain A and B proteins and UL16-binding proteins (MICA/B and ULBP, respectively). The abundance of these membrane-associated NKG2D ligands is increased on the cell surface upon infection or oncogenic transformation. Vantourout et al. found that common anticancer therapies that inhibit the epidermal growth factor receptor (EGFR) or the mitogen-activated protein kinase (MAPK) pathway in tumor cells also decreased the surface abundance of these NKG2D ligands, which could result in loss of immune targeting of these cells. Exposure of skin cells to ultraviolet B radiation (UVB) activates EGFR signaling, and exposure of cultured human primary and HaCat keratinocytes to UVB increased the amount of MICA, MICB, and ULBP2 at the cell surface. Although UVB can cause DNA damage, other DNA-damaging agents did not increase the abundance of MICA mRNA in HaCat cells, indicating that the induction of MICA was independent of pathways involved in responding to DNA damage. Treating HaCat cultures with AG1478 (a tyrosine kinase inhibitor with selectivity for EGFR) blocked UVB-induced MICA expression; in contrast, adding EGF to HaCat cells, but not to EGFR-deficient HCT116 cells, induced MICA expression. Therapeutically used EGFR inhibitors or inhibitors of MAPK signaling prevented the EGF-stimulated increase in the cell surface abundance of NKG2D ligands. EGF stabilized MICA and MICB mRNAs in HaCat cells and induced the nuclear exclusion of AUF1, an mRNA decay factor. Overexpression of AUF1 in HaCat cells decreased the cell surface abundance of NKG2D ligands. In panels of primary breast cancer cell lines and patient tumors, the expression of NKG2D ligand-coding genes inversely correlated with that of the gene encoding AUF1 but positively correlated with that of EGFR. Primary peripheral blood mononuclear cells had increased surface abundance of markers of NK cell activation when cocultured with HaCat cells that were pretreated with EGF compared with those that were untreated, and an antibody against NGK2D prevented this effect. The findings show that some cancer therapies may be a double-edged sword by blocking pathways that mediate tumor growth and immune recognition.

P. Vantourout, C. Willcox, A. Turner, C. M. Swanson, Y. Haque, O. Sobolev, A. Grigoriadis, A. Tutt, A. Hayday, Immunological visibility: Posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Sci. Transl. Med. 6, 231ra49 (2014). [PubMed]