LSECtin on tumor-associated macrophages enhances breast cancer stemness via interaction with its receptor BTN3A3

Cell Res. 2019 May;29(5):365-378. doi: 10.1038/s41422-019-0155-6. Epub 2019 Mar 11.

Abstract

Macrophages have been suggested to contribute to constructing a cancer stem cell (CSC) niche. However, whether and how macrophages regulate the activity of CSCs through juxtacrine signaling are poorly understood. Here we report LSECtin, a transmembrane protein highly expressed on tumor-associated macrophages (TAMs), enhances stemness of breast cancer cells (BCCs). We identified BTN3A3, a B7 family member with previously unknown functions as the receptor for LSECtin on BCCs responsible for stemness-promoting effect of LSECtin. In mice bearing human tumor xenografts, either macrophage-specific ablation of LSECtin or silencing of BTN3A3 in BCCs decreased CSC frequency and tumor growth. Admixture of LSECtin-positive macrophages increased the tumorigenic activity of BCCs dependent on BTN3A3. Disruption of the LSECtin-BTN3A3 axis with BTN3A3-Fc or anti-BTN3A3 mAb has a therapeutic effect on breast cancer. These findings define a juxtacrine signaling mechanism by which TAMs promote cancer stemness. Targeting this axis in the CSC niche may provide potential therapies to breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Butyrophilins / antagonists & inhibitors
  • Butyrophilins / genetics
  • Butyrophilins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Lectins, C-Type / deficiency
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Butyrophilins
  • CD68 antigen, human
  • Lectins, C-Type
  • RNA, Small Interfering