title: A novel strategy for evasion of NK cell immunity by tumours expressing core2 O-glycans.
abstract: The O-glycan branching enzyme, core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N-acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis.
authors.affiliation: Department of Biochemistry, Oyokyo Kidney Research Institute, Hirosaki, Japan. tsuboi@oyokyo.jp
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuboi
authors.forename: Mihoko
authors.initials: M
authors.lastname: Sutoh
authors.forename: Shingo
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yoneyama
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Mori
authors.forename: Takuya
authors.initials: T
authors.lastname: Koie
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hisao
authors.initials: H
authors.lastname: Saitoh
authors.forename: Kanemitsu
authors.initials: K
authors.lastname: Yamaya
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Funyu
authors.forename: Minoru
authors.initials: M
authors.lastname: Fukuda
authors.forename: Chikara
authors.initials: C
authors.lastname: Ohyama
mesh_terms: D037502:Galectin 3 / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000276:immunology*
chemical_list: D037502:Galectin 3; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011134:Polysaccharides; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase