Modulation of pancreatic tumor immunity by NKG2D T cells through MICB shedding

Abstract

Abstract Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce the activation of immune cells or tumor escape responses, depending on their expression. Human pancreatic cancer cells, Panc-1, express membrane MICA/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. The findings revealed that downregulation of MICB reduced sMICB, downregulated mMICB, maintained activation of NKG2DLow T cells, and inhibited activation of NKG2DHigh T cells. To maintain mMICB expression and reduce sMICB expression, we inhibited ADAM, a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented by ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. These results elucidate the mechanism of immune escape via sMICB and show promising potential for the activation of NKG2DLow T cells within the tumor microenvironment.