TY - JOUR
T1 - A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice
AU - Fang, Jinxu
AU - Xiao, Liang
AU - Joo, Kye Il
AU - Liu, Yarong
AU - Zhang, Chupei
AU - Liu, Shuanglong
AU - Conti, Peter S.
AU - Li, Zibo
AU - Wang, Pin
N1 - Publisher Copyright:
© 2015 UICC.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - 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. What's new? As a key component of tumor stroma, tumor-associated fibroblasts (TAFs) promote malignant growth, angiogenesis, invasion, and metastasis. Fibroblast activation protein (FAP), a surface protein that is exceedingly expressed in TAFs, could function as an attractive target for cancer therapy in a broad range of cancers. In this study, the authors developed a novel immunotoxin αFAP-PE38 targeting the nonmalignant compartment of solid tumors and demonstrated its potent antitumor activity as well as the enhanced therapeutic efficacy of this immunotoxin with paclitaxel. These studies pave the way for applying the combination of FAP-targeting immunotoxin and chemotherapeutic agent as a promising new strategy to enhance clinical application of immunotoxin-based therapies.
AB - 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. What's new? As a key component of tumor stroma, tumor-associated fibroblasts (TAFs) promote malignant growth, angiogenesis, invasion, and metastasis. Fibroblast activation protein (FAP), a surface protein that is exceedingly expressed in TAFs, could function as an attractive target for cancer therapy in a broad range of cancers. In this study, the authors developed a novel immunotoxin αFAP-PE38 targeting the nonmalignant compartment of solid tumors and demonstrated its potent antitumor activity as well as the enhanced therapeutic efficacy of this immunotoxin with paclitaxel. These studies pave the way for applying the combination of FAP-targeting immunotoxin and chemotherapeutic agent as a promising new strategy to enhance clinical application of immunotoxin-based therapies.
KW - breast cancer
KW - fibroblast activation protein
KW - immunotoxin
KW - positron emission tomography
KW - tumor microenvironment
KW - tumor-associated fibroblast
UR - http://www.scopus.com/inward/record.url?scp=84954380288&partnerID=8YFLogxK
U2 - 10.1002/ijc.29831
DO - 10.1002/ijc.29831
M3 - Article
C2 - 26334777
AN - SCOPUS:84954380288
SN - 0020-7136
VL - 138
SP - 1013
EP - 1023
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 4
ER -