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

• Main Authors: Fernanda I Staquicini, Amin Hajitou, Wouter HP Driessen, Bettina Proneth, Marina Cardó-Vila, Daniela I Staquicini, Christopher Markosian, Maria Hoh, Mauro Cortez, Anupama Hooda-Nehra, Mohammed Jaloudi, Israel T Silva, Jaqueline Buttura, Diana N Nunes, Emmanuel Dias-Neto, Bedrich Eckhardt, Javier Ruiz-Ramírez, Prashant Dogra, Zhihui Wang, Vittorio Cristini, Martin Trepel, Robin Anderson, Richard L Sidman, Juri G Gelovani, Massimo Cristofanilli, Gabriel N Hortobagyi, Zaver M Bhujwalla, Stephen K Burley, Wadih Arap, Renata Pasqualini
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2021-06-01
• Series: eLife
• Subjects: vitamin D receptor; tumor-associated macrophage; triple-negative breast cancer
• Online Access: https://elifesciences.org/articles/65145

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.