Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 138, Issue 4, Pages 1013-1023Publisher
WILEY-BLACKWELL
DOI: 10.1002/ijc.29831
Keywords
immunotoxin; fibroblast activation protein; tumor-associated fibroblast; breast cancer; tumor microenvironment; positron emission tomography
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Funding
- National Institutes of Health [R01AI068978, R01CA170820, R01EB017206, P01CA132681]
- Joint Center for Translational Medicine, National Cancer Institute [P30CA014089]
- Ming Hsieh Institute for Research on Engineering Medicine for Cancer
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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 alpha FAP-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 alpha FAP-PE38 and paclitaxel potently inhibited tumor growth in vivo. Our findings highlight the potential use of immunotoxin alpha FAP-PE38 to deplete FAP-expressing TAFs and thus provide a rationale for the use of this immunotoxin in cancer therapy.
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