Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 01, 2021
- Source ID
- 10.7554/elife.65145
Entities
People
- Amin Hajitou
- Anupama Hooda-nehra
- Bedrich Eckhardt
- Bettina Proneth
- Christopher Markosian
- Daniela I. Staquicini
- Diana N Nunes
- Emmanuel Dias-neto
- Fernanda I. Staquicini
- Gabriel N Hortobagyi
- Israel T Silva
- Jaqueline Buttura
- Javier Ruiz-ramírez
- Juri Gelovani
- Maria Hoh
- Marina Cardo-vila
- Martin Trepel
- Massimo Cristofanilli
- Mauro Cortez
- Mohammed Jaloudi
- Prashant Dogra
- Renata Pasqualini
- Richard L. Sidman
- Robin Anderson
- Stephen K Burley
- Vittorio Cristini
- Wadih Arap
- Wouter Hp Driessen
- Zaver M. Bhujwalla
- Zhihui Wang
Organizations
- A.C. Camargo Cancer Center
- Harvard Medical School
- Helmholtz Zentrum München
- Houston Methodist Hospital
- Imperial College London
- Johns Hopkins School of Medicine
- National Institutes of Health
- National Science Foundation
- New Jersey Medical School
- Northwestern University
- Rutgers University
- Rutgers University–New Brunswick
- Susan G. Komen for the Cure
- São Paulo Research Foundation
- United States Department of Defense
- United States Department of Energy
- University Medical Center Hamburg-Eppendorf
- University of Arizona
- University of California, San Diego
- University of São Paulo
- University of Texas at Austin
- Wayne State University