FUT8-mediated Aberrant N-glycosylation of B7H3 Suppresses the Immune Response in Triple-negative Breast Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 12

PMID 33976130

Citations 69

Authors

Yun Huang

Hai-Liang Zhang

Zhi-Ling Li

Tian Du

Yu-Hong Chen

Yan Wang

Huan-He Ni

Kai-Ming Zhang

Jia Mai

Bing-Xin Hu

Jun-Hao Huang

Li-Huan Zhou

Dong Yang

Xiao-Dan Peng

Gong-Kan Feng

Jun Tang

Xiao-Feng Zhu

Rong Deng

Affiliations

Soon will be listed here.

Abstract

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.

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