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

• Published in: Scientific Reports
• Main Authors: Hitoshi Toyoda, Atsuo Kuramasu, Masahiro Hosonuma, Masakazu Murayama, Yoichiro Narikawa, Junya Isobe, Yuta Baba, Kohei Tajima, Eiji Funayama, Midori Shida, Yuki Maruyama, Aya Sasaki, Yuya Hirasawa, Toshiaki Tsurui, Hirotsugu Ariizumi, Tomoyuki Ishiguro, Risako Suzuki, Sei Kobayashi, Atsushi Horiike, Noriko Hida, Takehiko Sambe, Koji Nobe, Satoshi Wada, Hitome Kobayashi, Mayumi Tsuji, Shinichi Kobayashi, Takuya Tsunoda, Yoshifumi Kudo, Yuji Kiuchi, Kiyoshi Yoshimura
• Format: Article
• Language: English
• Published: Nature Portfolio 2024-10-01
• Subjects: NKG2DL; NKG2D; T cell; MICB; ADAM; Pancreatic tumor
• Online Access: https://doi.org/10.1038/s41598-024-73712-1

Abstract 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 NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2DLow T cell activation, and inhibited NKG2DHigh 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 NKG2DLow T cells was maintained. In vivo xenograft model revealed that NKG2DHigh T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2DLow T cells within the tumor microenvironment.