MHC class I polypeptide-related sequence B shedding modulates pancreatic tumor immunity via the activation of NKG2D(Low) 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 polypeptide-related sequence 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 and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA 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. In vivo xenograft model revealed that NKG2D(High) T cells have superior anti-tumor activity. 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.