A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice.
Fibroblast activation protein (FAP) is highly expressed in the tumor-associated fibroblasts (TAFs) of most human epithelial cancers. FAP plays a critical role in tumorigenesis and cancer progression, which makes it a promising target for novel anticancer therapy. However, mere abrogation of FAP enzymatic activity by small molecules is not very effective in inhibiting tumor growth. In this study, we have evaluated a novel immune-based approach to specifically deplete FAP-expressing TAFs in a mouse 4T1 metastatic breast cancer model. Depletion of FAP-positive stromal cells by FAP-targeting immunotoxin αFAP-PE38 altered levels of various growth factors, cytokines, chemokines and matrix metalloproteinases, decreased the recruitment of tumor-infiltrating immune cells in the tumor microenvironment and suppressed tumor growth. In addition, combined treatment with αFAP-PE38 and paclitaxel potently inhibited tumor growth in vivo. Our findings highlight the potential use of immunotoxin αFAP-PE38 to deplete FAP-expressing TAFs and thus provide a rationale for the use of this immunotoxin in cancer therapy.
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.
Jinxu
J
Fang
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.
Liang
L
Xiao
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.
Kye-Il
KI
Joo
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.
Yarong
Y
Liu
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.
Chupei
C
Zhang
Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA.
Shuanglong
S
Liu
Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA.
Peter S
PS
Conti
Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA.
Zibo
Z
Li
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.|Department of Biomedical Engineering, University of Southern California, Los Angeles, CA.|Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA.
Pin
P
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D041702:BALB 3T3 Cells; D001943:Breast Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
D000970:Antineoplastic Agents; D010450:Endopeptidases; D018093:Gelatinases; D000922:Immunotoxins; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
breast cancer; fibroblast activation protein; immunotoxin; positron emission tomography; tumor microenvironment; tumor-associated fibroblast