TY - JOUR
T1 - Targeting a cell surface vitamin d receptor on tumor-associated macrophages in triple-negative breast cancer
AU - Staquicini, Fernanda I.
AU - Hajitou, Amin
AU - Driessen, Wouter H.P.
AU - Proneth, Bettina
AU - Cardó-Vila, Marina
AU - Staquicini, Daniela I.
AU - Markosian, Christopher
AU - Hoh, Maria
AU - Cortez, Mauro
AU - Hooda-Nehra, Anupama
AU - Jaloudi, Mohammed
AU - Silva, Israel T.
AU - Buttura, Jaqueline
AU - Nunes, Diana
AU - Dias-Neto, Emmanuel
AU - Eckhardt, Bedrich
AU - Ruiz-Ramírez, Javier
AU - Dogra, Prashant
AU - Wang, Zhihui
AU - Cristini, Vittorio
AU - Trepel, Martin
AU - Anderson, Robin
AU - Sidman, Richard L.
AU - Gelovani, Juri G.
AU - Cristofanilli, Massimo
AU - Hortobagy, Gabriel
AU - Bhujwalla, Zaver M.
AU - Burley, Stephen
AU - Arap, Wadih
AU - Pasqualini, Renata
N1 - Funding Information:
This work was supported by the US DOD IMPACT grant W81XWH-09-1-0224 and by serial awards from the Gillson-Longenbaugh Foundation and the Susan G Komen Breast Cancer Foundation (to WA and RP). The RCSB Protein Data Bank is supported by grants to SKB from the National Science Foundation (DBI-1832184), the NIH (R01GM133198), and the US DOE (DE-SC0019749). This work has also been supported by the National Science Foundation Grant DMS-1930583 (ZW, VC), NIH Grants 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, VC, WA, RP), 1R01CA222007 (ZW, VC), and U54CA210181 (ZW, VC). MC was partially funded by FAPESP (2012/ 24105-3, 2020/13562?0). We thank Dr. Helen Pickersgill (Life Science Editors) for professional editing and Dr. Webster K Cavenee, Dr. Sylvia Christakos, and Dr. E Helene Sage for critical reading of the manuscript. JGG, WA, and RP are founders and equity stockholders of PhageNova Bio, which has licensed reagents disclosed in this manuscript. AH, WHPD, BP, WA and RP are entitled to royalty payments from this licensing agreement. RP is the Chief Scientific Officer and a paid consultant for PhageNova Bio. WA and RP are partially supported by a Sponsored Research Agreement from PhageNova Bio. AH, JGG, WA, and RP are inventors on issued and pending patent applications related to technology disclosed in this manuscript and will be entitled to royalties if licensing or com-mercialization occurs. WA and RP are also founders and equity holders of MBrace Therapeutics. RP serves as a Board Member of MBrace Therapeutics. These arrangements are managed and moni-tored in accordance with the established institutional conflict of interest policies of Rutgers, the State University of New Jersey. MC is a consultant for CytoDyn, Sermonix Pharmaceuticals, G1 Ther-apeutics, Foundation Medicine, Domp?, ArcherDX and Menarini. MC also receives honoraria/travel grants from Pfizer, Lilly, Novartis, Sermonix Pharmaceuticals, Foundation Medicine and Menarini. Other authors declare that they have no competing interests.
Funding Information:
This work was supported by the US DOD IMPACT grant W81XWH-09-1-0224 and by serial awards from the Gillson-Longenbaugh Foundation and the Susan G Komen Breast Cancer Foundation (to WA and RP). The RCSB Protein Data Bank is supported by grants to SKB from the National Science Foundation (DBI-1832184), the NIH (R01GM133198), and the US DOE (DE-SC0019749). This work has also been supported by the National Science Foundation Grant DMS-1930583 (ZW, VC), NIH Grants 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, VC, WA, RP), 1R01CA222007 (ZW, VC), and U54CA210181 (ZW, VC). MC was partially funded by FAPESP (2012/ 24105-3, 2020/13562–0). We thank Dr. Helen Pickersgill (Life Science Editors) for professional editing and Dr. Webster K Cavenee, Dr. Sylvia Christakos, and Dr. E Helene Sage for critical reading of the manuscript. JGG, WA, and RP are founders and equity stockholders of PhageNova Bio, which has licensed reagents disclosed in this manuscript. AH, WHPD, BP, WA and RP are entitled to royalty payments from this licensing agreement. RP is the Chief Scientific Officer and a paid consultant for PhageNova Bio. WA and RP are partially supported by a Sponsored Research Agreement from PhageNova Bio. AH, JGG, WA, and RP are inventors on issued and pending patent applications related to technology disclosed in this manuscript and will be entitled to royalties if licensing or commercialization occurs. WA and RP are also founders and equity holders of MBrace Therapeutics. RP serves as a Board Member of MBrace Therapeutics. These arrangements are managed and monitored in accordance with the established institutional conflict of interest policies of Rutgers, the State University of New Jersey. MC is a consultant for CytoDyn, Sermonix Pharmaceuticals, G1 Therapeutics, Foundation Medicine, Dompé, ArcherDX and Menarini. MC also receives honoraria/travel grants from Pfizer, Lilly, Novartis, Sermonix Pharmaceuticals, Foundation Medicine and Menarini. Other authors declare that they have no competing interests.
Publisher Copyright:
© Staquicini et al.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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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U2 - 10.7554/eLife.65145
DO - 10.7554/eLife.65145
M3 - Article
C2 - 34060472
AN - SCOPUS:85107449683
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e65145
ER -