FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer

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 () and Rong Deng ()
Additional contact information
Yun Huang: Sun Yat-sen University Cancer Center
Hai-Liang Zhang: Sun Yat-sen University Cancer Center
Zhi-Ling Li: Sun Yat-sen University Cancer Center
Tian Du: Sun Yat-sen University Cancer Center
Yu-Hong Chen: Sun Yat-sen University Cancer Center
Yan Wang: Sun Yat-sen University Cancer Center
Huan-He Ni: Sun Yat-sen University Cancer Center
Kai-Ming Zhang: Sun Yat-sen University Cancer Center
Jia Mai: Sun Yat-sen University Cancer Center
Bing-Xin Hu: Sun Yat-sen University Cancer Center
Jun-Hao Huang: Sun Yat-sen University Cancer Center
Li-Huan Zhou: Sun Yat-sen University Cancer Center
Dong Yang: Sun Yat-sen University Cancer Center
Xiao-Dan Peng: Sun Yat-sen University Cancer Center
Gong-Kan Feng: Sun Yat-sen University Cancer Center
Jun Tang: Sun Yat-sen University Cancer Center
Xiao-Feng Zhu: Sun Yat-sen University Cancer Center
Rong Deng: Sun Yat-sen University Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22618-x

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