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Staquicini, F.I.* ; Hajitou, A.* ; Driessen, W.H.* ; Proneth, B. ; Cardó-Vila, M.* ; Staquicini, D.I.* ; Markosian, C.* ; Hoh, M.* ; Cortez, M.* ; Hooda-Nehra, A.* ; Jaloudi, M.* ; Silva, I.T.* ; Buttura, J.* ; Nunes, D.* ; Dias-Neto, E.* ; Eckhardt, B.* ; Ruiz-Ramírez, J.* ; Dogra, P.* ; Wang, Z.* ; Cristini, V.* ; Trepel, M.* ; Anderson, R.* ; Sidman, R.L.* ; Gelovani, J.G.* ; Cristofanilli, M.* ; Hortobagy, G.* ; Bhujwalla, Z.M.* ; Burley, S.* ; Arap, W.* ; Pasqualini, R.*

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

eLife 10:e65145 (2021)

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	Open Access Gold

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Medicine ; Mouse ; Triple-negative Breast Cancer ; Tumor-associated Macrophage ; Vitamin D Receptor; In-vivo; Structural Basis; Mouse Model; Expression; Peptide; Disparities; Mechanism; Delivery; Features; Complex

ISSN (print) / ISBN 2050-084X

e-ISSN 2050-084X

Journal eLife

Quellenangaben Volume: 10, Article Number: e65145

Publisher eLife Sciences Publications

Publishing Place Sheraton House, Castle Park, Cambridge, Cb3 0ax, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)

Grants NCI NIH HHS
U.S. Department of Defense
U.S. Department of Energy
NIGMS NIH HHS
NIH HHS
National Science Foundation