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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7 Antigens / genetics
  • B7 Antigens / metabolism*
  • Cell Line, Tumor
  • Female
  • Fucose / metabolism
  • Fucosyltransferases / genetics
  • Fucosyltransferases / metabolism*
  • Gene Knockout Techniques
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Immunity
  • Kaplan-Meier Estimate
  • Mice, Inbred BALB C
  • Mice, SCID
  • Polysaccharides / metabolism
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / therapy
  • Xenograft Model Antitumor Assays / methods

Substances

  • B7 Antigens
  • CD276 protein, human
  • Polysaccharides
  • Fucose
  • Fucosyltransferases
  • Glycoprotein 6-alpha-L-fucosyltransferase