Fang Jinxu, Xiao Liang, Joo Kye-Il, Liu Yarong, Zhang Chupei, Liu Shuanglong, Conti Peter S, Li Zibo, Wang Pin
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA.
Molecular Imaging Center, Department of Radiology, University of Southern California, Los Angeles, CA.
Int J Cancer. 2016 Feb 15;138(4):1013-23. doi: 10.1002/ijc.29831. Epub 2015 Sep 14.
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.
成纤维细胞活化蛋白（FAP）在大多数人类上皮癌的肿瘤相关成纤维细胞（TAF）中高表达。FAP在肿瘤发生和癌症进展中起关键作用，这使其成为新型抗癌治疗的一个有前景的靶点。然而，仅通过小分子消除FAP酶活性在抑制肿瘤生长方面并不是非常有效。在本研究中，我们评估了一种基于免疫的新方法，以在小鼠4T1转移性乳腺癌模型中特异性清除表达FAP的TAF。通过靶向FAP的免疫毒素αFAP-PE38消耗FAP阳性基质细胞，改变了各种生长因子、细胞因子、趋化因子和基质金属蛋白酶的水平，减少了肿瘤微环境中肿瘤浸润免疫细胞的募集，并抑制了肿瘤生长。此外，αFAP-PE38与紫杉醇联合治疗在体内有效抑制了肿瘤生长。我们的研究结果突出了免疫毒素αFAP-PE38在消耗表达FAP的TAF方面的潜在用途，从而为在癌症治疗中使用这种免疫毒素提供了理论依据。
