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

Author(s):Show less -

Staquicini, I, Fernanda ; Hajitou, Amin ^[1] ; Driessen, Wouter H. P. ^{[2, 3]} ; Proneth, Bettina ^[4] ; Cardo-Vila, Marina ^{[5, 6]} ; Staquicini, I, Daniela ; Markosian, Christopher ^{[7, 8]} ; Hoh, Maria ^{[9, 10]} ; Cortez, Mauro ^[11] ; Hooda-Nehra, Anupama ^{[12, 7]} ; Jaloudi, Mohammed ^{[12, 7]} ; Silva, Israel T. ^[13] ; Buttura, Jaqueline ^[13] ; Nunes, Diana ^[14] ; Dias-Neto, Emmanuel ^{[13, 14]} ; Eckhardt, Bedrich ^[15] ; Ruiz-Ramirez, Javier ^[16] ; Dogra, Prashant ^[16] ; Wang, Zhihui ^[16] ; Cristini, Vittorio ^[16] ; Trepel, Martin ^{[17, 18]} ; Anderson, Robin ^[15] ; Sidman, Richard L. ^[19] ; Gelovani, Juri G. ^{[20, 21, 22, 23]} ; Cristofanilli, Massimo ^[24] ; Hortobagy, Gabriel ^[25] ; Bhujwalla, Zaver M. ^[9] ; Burley, Stephen ^{[26, 27, 28]} ; Arap, Wadih ^{[12, 7]} ; Pasqualini, Renata ^{[7, 8]}

Affiliation:Show less -

^[1] Imperial Coll London, Dept Brain Sci, Phage Therapy Grp, London - England

^[2] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 - USA

^[3] Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Basel - Switzerland

^[4] Helmholtz Zentrum Muenchen, Inst Metab & Cell Death, Neuherberg - Germany

^[5] Univ Arizona, Canc Ctr, Dept Cellular & Mol Med, Tucson, AZ - USA

^[6] Univ Arizona, Canc Ctr, Dept Otolaryngol Head & Neck Surg, Tucson, AZ - USA

^[7] Staquicini, Daniela, I, Staquicini, Fernanda, I, Rutgers Canc Inst New Jersey, Newark, NJ 07103 - USA

^[8] Staquicini, Daniela, I, Staquicini, Fernanda, I, Rutgers New Jersey Med Sch, Dept Radiat Oncol, Div Canc Biol, Newark, NJ 07103 - USA

^[9] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Div Canc Imaging Res, Baltimore, MD - USA

^[10] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO - USA

^[11] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo, SP - Brazil

^[12] Rutgers New Jersey Med Sch, Dept Med, Div Hematol Oncol, Newark, NJ 07103 - USA

^[13] AC Camargo Canc Ctr, Lab Computat Biol, Sao Paulo, SP - Brazil

^[14] AC Camargo Canc Ctr, Lab Med Genom, Sao Paulo, SP - Brazil

^[15] Olivia Newton John Canc Res Inst, Translat Breast Canc Program, Melbourne, Vic - Australia

^[16] Houston Methodist Res Inst, Math Med Program, Houston, TX - USA

^[17] Univ Med Ctr Hamburg Eppendorf, Dept Oncol & Hematol, Hamburg - Germany

^[18] Univ Med Ctr Augsburg, Dept Oncol & Hematol, Augsburg - Germany

^[19] Harvard Med Sch, Dept Neurol, Boston, MA 02115 - USA

^[20] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI - USA

^[21] Wayne State Univ, Coll Engn, Dept Biomed Engn, Detroit, MI - USA

^[22] Wayne State Univ, Sch Med, Dept Neurosurg, Detroit, MI - USA

^[23] United Arab Emirates Univ, Off Provost, Al Ain - U Arab Emirates

^[24] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 - USA

^[25] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 - USA

^[26] Rutgers Canc Inst New Jersey, New Brunswick, NJ - USA

^[27] Univ Calif San Diego, San Diego Supercomp Ctr, Res Collab Struct Bioinformat Prot Data Ba, La Jolla, CA 92093 - USA

^[28] State Univ New Jersey, Inst Quantitat Biomed, Res Collab Struct Bioinformat Prot Data Ba, Rutgers, Piscataway, NJ - USA

• Document type: Journal article
• Source: eLIFE; v. 10, JUN 1 2021.
• Web of Science Citations: 0

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 nonmalignant 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. (AU)

• FAPESP's process: 12/24105-3 - Immunobiology of Leishmania spp.: study of the role of CD200 and biogenesis of parasitophorous vacuole in fagocitic cells infected by Leishmania
• Grantee: Mauro Javier Cortez Véliz
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/13562-0 - Unveiling the role of the immune checkpoint ligand CD200 in the host infection by Leishmania spp.
• Grantee: Mauro Javier Cortez Véliz
• Support Opportunities: Regular Research Grants