The antitumor activities of cytolytic T lymphocytes and natural killer cells are being increasingly investigated and exploited in cancer immunotherapy. One mechanism by which these cells recognize tumor cells is by engagement of NKG2D, an activating receptor on cytolytic T lymphocytes and natural killer cells, by MICA/B and ULBP family stress antigens.
In a study reported in Science Translational Medicine, Vantourout and colleagues showed that activation of EGFR is responsible for surface upregulation of NKG2D ligands in human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor exposure. EGFR activation results in intracellular relocalization of adenylate-uridylate (AU)-rich element RNA-binding protein 1 (AUF1); AUF1 proteins normally destabilize NKG2D ligand mRNAs by targeting an AU-rich element that is conserved in the 3′ ends of most human, but not murine, NKG2D ligand genes. NKG2D ligand expression was positively correlated with EGFR expression in primary human carcinomas and was reduced by treatment with clinically available EGFR inhibitors.
Thus, as noted by the investigators, stress-induced activation of EGFR both regulates cell growth and modulates immunologic visibility of cancer cells. They concluded, “[T]herapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.” ■
Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.