Journal Article

A novel strategy for evasion of NK cell immunity by tumours expressing core2 O-glycans

Saitoh, Hisao, Nakamura, Toshiya, Hiraoka, Nobuyoshi, Sutoh, Mihoko, Fukuda, Minoru, Hatakeyama, Shingo, Horikawa, Yohei, Hashimoto, Yasuhiro, Yamaya, Kanemitsu, Tsuboi, Shigeru, Mori, Kazuyuki, Yoneyama, Takahiro, Funyu, Tomihisa, Koie, Takuya, Ohyama, Chikara, Habuchi, Tomonori

2011

Overview

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. This paper illuminates a new mechanism for tumour cell evasion from the immune surveillance. Molecular analyses reveal modifications of the NKG2D‐NKG2DL system that prevent natural killer cell activation.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: Bladder / core2 O-glycans / Enzymes / Galectin 3 - metabolism / Gene expression / Glycoproteins / Histocompatibility Antigens Class I - metabolism / Immune Evasion / Killer Cells, Natural - immunology / Metastasis / MICA / Molecular biology / N-Acetylglucosaminyltransferases - metabolism / NK cell immunity / NK Cell Lectin-Like Receptor Subfamily K - metabolism / NKG2D / Polysaccharides - metabolism / Tumors / tumour metastasis / Urinary Bladder Neoplasms - chemistry / Urinary Bladder Neoplasms - enzymology / Urinary Bladder Neoplasms - immunology