MHC class I chain-related genes B shedding modulates pancreatic tumor immunity via the activation of NKG2DLow T cells

Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I chain-related genes A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2D-low T cells (NKG2D ^Low T cells) and inhibits the activation signal from mMICB to NKG2D. Our findings revealed that the downregulation of MICB expression reduced sMICB level, downregulated mMICB expression, maintained NKG2D ^Low T cell activation, and inhibited NKG2D ^High T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2D ^Low T cells was maintained. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2D ^Low T cells within the tumor microenvironment.