title: A mechanism for evasion of CTL immunity by altered O-glycosylation of HLA class I.
abstract: Anti-tumour immunity by cytotoxic T-lymphocytes (CTLs) is essential to suppress tumour progression. Cancer cells that evade CTL immunity proliferate in the host, promoting metastasis, but mechanisms underlying this capacity remain unknown. Here we report that bladder cancer cells metastasized to lymph nodes evade CTL immunity by a new mechanism via altered glycosylation. CTLs normally recognize and kill cancer cells presenting antigenic peptides on human leukocyte antigen (HLA) class I. We show bladder cancer cells expressing the O-glycan processing enzyme, core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) exhibit HLA class I O-glycan modified with poly-N-acetyllactosamine and are highly susceptible to CTL. In those cells, poly-N-acetyllactosamine on HLA class I O-glycan binds galectin-3 to form a cell-surface molecular lattice, enabling efficient cell-surface retention of HLA class I. In contrast, bladder cancer cells in which C2GnT is downregulated show decreased levels of poly-N-acetyllactosamine on HLA class I O-glycans, attenuating lattice formation and reducing the cell-surface half-life of HLA class I. These tumour cells present antigenic peptides less efficiently, thereby evading CTL lysis and facilitating metastasis.
authors.affiliation: Department of Cancer Immunology and Cell Biology, Oyokyo Kidney Research Institute, Hirosaki, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Sutoh Yoneyama
authors.affiliation: Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tobisawa
authors.affiliation: Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Department of Cancer Immunology and Cell Biology, Oyokyo Kidney Research Institute, Hirosaki, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Anatomic Pathology, Hirosaki University Hospital, Hirosaki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tone
authors.affiliation: Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yota
authors.initials: Y
authors.lastname: Tatara
authors.affiliation: Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kakizaki
authors.affiliation: Department of Cancer Immunology and Cell Biology, Oyokyo Kidney Research Institute, Hirosaki, Japan.
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Funyu
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Urology, Yamagata Prefectural Central Hospital, Yamagata, Japan.
authors.forename: Senji
authors.initials: S
authors.lastname: Hoshi
authors.affiliation: Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Ohyama
authors.affiliation: Department of Cancer Immunology and Cell Biology, Oyokyo Kidney Research Institute, Hirosaki, Japan.|Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuboi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D006031:Glycosylation; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D015395:Histocompatibility Antigens Class I; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase
keywords: O-glycan; cancer immunology; cytotoxic T-lymphocyte (CTL); galectin; immune evasion