Two Opposite Roles of Core 2 O-Glycans in Evasion Mechanisms of Tumor Immunity

Abstract

Tumor immunity has a two-stage defense system consisting of natural killer (NK) immunity for primary tumor and cytotoxic T lymphocyte (CTL) immunity for the metastatic lesions. However, cancer exerts the versatile immune evasion strategies to predominate over this two-stage defense. A series of our studies revealed that bladder cancer cells evade each tumor immune system by different evasion strategies using altered O-glycosylation. β-1,6-N-acetylglucosaminyltransferase (C2GnT) which adds N-acetylglucosamine to N-acetylgalactosamine forms a branched structure called core 2 O-glycans on cell-surface glycoproteins. To elucidate the roles of core 2 O-glycans in bladder cancer metastasis, we analyzed C2GnT expression in cancer cells in bladder (primary tissue) and cancer cells in lymph node (target organ). We showed that bladder cancer cells evade NK tumor immunity by upregulating C2GnT expression and CTL immunity by downregulating C2GnT expression. C2GnT-positive cancer cells survive NK cell attack in the primary tissue, resulting in acquiring a high-metastatic phenotype. On the other hand, C2GnT-negative cancer cells evade CTL attack, resulting in indefinite proliferation in the target organs such as lymph node. This review highlights two opposite roles of core 2 O-glycans in the evasion mechanisms of the attack by different effector cells.