Targeting a Cell Surface Vitamin D Receptor on Tumor-associated Macrophages in Triple-negative Breast Cancer

Overview

Journal Elife

Specialty Biology

Date 2021 Jun 1

PMID 34060472

Citations 18

Authors

Fernanda I Staquicini

Amin Hajitou

Wouter Hp Driessen

Bettina Proneth

Marina Cardo-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-Ramirez

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

Affiliations

Soon will be listed here.

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.

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