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

eLife

Juri G Gelovani¹  Gabriel Hortobagy²  Marina Cardó-Vila³  Richard L Sidman⁴  Martin Trepel⁵  Mauro Cortez⁶  Maria Hoh⁷  Zaver M Bhujwalla⁷  Bettina Proneth⁸  Jaqueline Buttura⁹  Israel T Silva⁹  Emmanuel Dias-Neto^1,10  Diana Nunes^1,11  Javier Ruiz-Ramírez^1,12  Zhihui Wang^1,12  Prashant Dogra^1,12  Vittorio Cristini^1,12  Amin Hajitou^1,13  Massimo Cristofanilli^1,14  Stephen Burley^1,15  Renata Pasqualini^1,16  Fernanda I Staquicini^1,16  Christopher Markosian^1,16  Daniela I Staquicini^1,16  Anupama Hooda-Nehra^1,17  Mohammed Jaloudi^1,17  Wadih Arap^1,17  Wouter HP Driessen^1,18  Bedrich Eckhardt^1,19  Robin Anderson^1,19 

[1] Department of Biomedical Engineering, College of Engineering, Wayne State University, Detroit, United States;Department of Oncology, School of Medicine, Wayne State University, Detroit, United States;Department of Neurosurgery, School of Medicine, Wayne State University, Detroit, United States;Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States;Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, University of Arizona, Tucson, United States;Department of Otolaryngology-Head and Neck Surgery, The University of Arizona Cancer Center, University of Arizona, Tucson, United States;Department of Neurology, Harvard Medical School, Boston, United States;Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Oncology and Hematology, University Medical Center Augsburg, Augsburg, Germany;Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, United States;Institute of Metabolism and Cell Death, Helmholtz Zentrum Muenchen, Neuherberg, Germany;Laboratory of Computational Biology, A.C. Camargo Cancer Center, São Paulo, Brazil;Laboratory of Computational Biology, A.C. Camargo Cancer Center, São Paulo, Brazil;Laboratory of Medical Genomics, A.C. Camargo Cancer Center, São Paulo, Brazil;Laboratory of Medical Genomics, A.C. Camargo Cancer Center, São Paulo, Brazil;Mathematics in Medicine Program, The Houston Methodist Research Institute, Houston, United States;Phage Therapy Group, Department of Brain Sciences, Imperial College London, London, United Kingdom;Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Chicago, Chicago, United States;Rutgers Cancer Institute of New Jersey, New Brunswick, United States;Research Collaboratory for Structural Bioinformatics Protein Data Bank, San Diego Supercomputer Center, University of California-San Diego, La Jolla, United States;Research Collaboratory for Structural Bioinformatics Protein Data Bank, Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, United States;Rutgers Cancer Institute of New Jersey, Newark, United States;Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, United States;Rutgers Cancer Institute of New Jersey, Newark, United States;Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, United States;The University of Texas M.D. Anderson Cancer Center, Houston, United States;Translational Breast Cancer Program, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;

关键词: vitamin D receptor;    tumor-associated macrophage;    triple-negative breast cancer;    Mouse;   

DOI  :  10.7554/eLife.65145

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY