Sutoh Yoneyama Mihoko, Tobisawa Yuki, Hatakeyama Shingo, Sato Misaki, Tone Kiyoshi, Tatara Yota, Kakizaki Ikuko, Funyu Tomihisa, Fukuda Minoru, Hoshi Senji, Ohyama Chikara, Tsuboi Shigeru
Department of Cancer Immunology and Cell Biology, Oyokyo Kidney Research Institute, Hirosaki, Japan.
Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
J Biochem. 2017 Jun 1;161(6):479-492. doi: 10.1093/jb/mvw096.
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.
细胞毒性T淋巴细胞（CTL）介导的抗肿瘤免疫对于抑制肿瘤进展至关重要。逃避CTL免疫的癌细胞在宿主体内增殖，促进转移，但其潜在机制尚不清楚。在这里，我们报告膀胱癌细胞转移至淋巴结后通过一种新的机制——糖基化改变来逃避CTL免疫。CTL通常识别并杀死在人类白细胞抗原（HLA）I类分子上呈递抗原肽的癌细胞。我们发现，表达O-聚糖加工酶核心2β-1,6-N-乙酰葡糖胺基转移酶（C2GnT）的膀胱癌细胞，其HLA I类分子的O-聚糖被多聚N-乙酰乳糖胺修饰，且对CTL高度敏感。在这些细胞中，HLA I类分子O-聚糖上的多聚N-乙酰乳糖胺与半乳糖凝集素-3结合形成细胞表面分子晶格，从而使HLA I类分子有效地保留在细胞表面。相反，C2GnT表达下调的膀胱癌细胞，其HLA I类分子O-聚糖上的多聚N-乙酰乳糖胺水平降低，晶格形成减弱，HLA I类分子在细胞表面的半衰期缩短。这些肿瘤细胞呈递抗原肽的效率降低，从而逃避CTL裂解并促进转移。
