2. Academic Validation
  3. FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer

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

  • Nat Commun. 2021 May 11;12(1):2672. doi: 10.1038/s41467-021-22618-x.
Yun Huang  # 1,  Hai-Liang Zhang  # 1,  Zhi-Ling Li  # 1,  Tian Du  # 1 2,  Yu-Hong Chen 1,  Yan Wang 1 2,  Huan-He Ni 1,  Kai-Ming Zhang 1 2,  Jia Mai 1,  Bing-Xin Hu 1,  Jun-Hao Huang 1 2,  Li-Huan Zhou 1 2,  Dong Yang 1,  Xiao-Dan Peng 1,  Gong-Kan Feng 1,  Jun Tang 3 4,  Xiao-Feng Zhu 5,  Rong Deng 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. tangjun@sysucc.org.cn.
  • 4 Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. tangjun@sysucc.org.cn.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. zhuxfeng@mail.sysu.edu.cn.
  • 6 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. dengrong@sysucc.org.cn.
  • # Contributed equally.
PMID: 33976130 DOI: 10.1038/s41467-021-22618-x
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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