Studies have highlighted molecular and cell
biological mechanisms of the NKG2D-NKG2D
ligand system in the activation of natural killer (NK) cell and T cell functions. In this study we explore the potential of genetic overexpression of human major histocompatibility complex class I chain-related gene A (
MICA), a powerful NKG2D
ligand, for the induction of NK cell-mediated antitumor immunity in a humanized murine model of
non-small cell lung cancer. Using tissue microarray technology we detected expression of
MICA in only 30% of the samples from patients with
lung cancer. Staining was always weak and focal, indicating that expression of
MICA is detectable but limited in human
lung cancer. Genetic overexpression of
MICA by means of adenoviral transduction or transfection of expression plasmids was feasible in cell lines in vitro, primary human
cancer tissue ex vivo, and in experimental human
cancers in vivo. The presence of
MICA on the surface of largely NK cell-resistant human
lung cancer cells reestablished NK cell susceptibility and provoked NK cell-mediated antitumor immunity by murine and human NK cells in two different
experimental therapy models. In this study we analyze the interaction of human NK cells with
MICA-positive human
cancer cells in an in vivo setting. Our data demonstrate that
MICA overexpression can function as NK cell-mediated
immunotherapy in experimental
lung cancer.