MHC class I polypeptide-related sequence B shedding modulates pancreatic tumor immunity via the activation of NKG2D Low T cells.

Autor: Toyoda H; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.; Department of Orthopedic Surgery, Showa University School of Medicine, Tokyo, 142-8555, Japan., Kuramasu A; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan., Hosonuma M; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan., Murayama M; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.; Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, 142-8555, Japan., Narikawa Y; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.; Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, 142-8555, Japan., Isobe J; Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Tokyo, 142-8555, Japan., Baba Y; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Tajima K; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan., Funayama E; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.; Division of Pharmacology, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, Tokyo, 142-8555, Japan., Shida M; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan., Maruyama Y; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan., Sasaki A; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan., Hirasawa Y; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Tsurui T; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Ariizumi H; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Ishiguro T; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Suzuki R; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Kobayashi S; Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, 142-8555, Japan., Horiike A; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Hida N; Division of Clinical Pharmacology, Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Division of Clinical Research and Development, Department of Clinical Pharmacy, School of Pharmacy, Showa University, Tokyo, 142-8555, Japan., Sambe T; Division of Clinical Research and Development, Department of Clinical Pharmacy, School of Pharmacy, Showa University, Tokyo, 142-8555, Japan., Nobe K; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.; Division of Pharmacology, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, Tokyo, 142-8555, Japan., Wada S; Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, 157-8577, Japan., Kobayashi H; Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, 142-8555, Japan., Tsuji M; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan., Kobayashi S; Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, 157-8577, Japan., Tsunoda T; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan., Kudo Y; Department of Orthopedic Surgery, Showa University School of Medicine, Tokyo, 142-8555, Japan., Kiuchi Y; Department of Pharmacology, Showa University School of Medicine, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan., Yoshimura K; Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan. kyoshim1@med.showa-u.ac.jp.; Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan. kyoshim1@med.showa-u.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 08; Vol. 14 (1), pp. 23401. Date of Electronic Publication: 2024 Oct 08.
DOI: 10.1038/s41598-024-73712-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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