Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer

Elife. 2021 Jun 1:10:e65145. doi: 10.7554/eLife.65145.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.

Keywords: medicine; mouse; triple-negative breast cancer; tumor-associated macrophage; vitamin D receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Enzyme Activation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Biological
  • Oligopeptides / pharmacology*
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism*
  • Signal Transduction
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Burden / drug effects
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / drug effects*
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism
  • Vitamin D-Binding Protein / genetics
  • Vitamin D-Binding Protein / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Ligands
  • Oligopeptides
  • Vitamin D-Binding Protein
  • Pdia3 protein, mouse
  • Protein Disulfide-Isomerases
  • PDIA3 protein, human

Associated data

  • GEO/GSE75688