Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment.

Abstract

Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibroblastic knockdown of FAP significantly impaired the ability of ICC-CAFs to promote ICC growth, MDSCs infiltration and angiogenesis, which was restored by adding exogenous CCL2. Furthermore, interestingly, the tumor-promoting effect of fibroblastic FAP is dependent on MDSCs via secretion of CCL2, as depletion of Gr-1+ cells reversed the restoring effects of exogenous CCL2 on tumor growth and angiogenesis. In vitro migration assay confirmed that exogenous CCL2 could rescue the impaired ability of ICC-Fbs to attract Gr-1+ cells caused by fibroblastic FAP knockdown. In contrast, fibroblastic FAP knockdown had no effect on ICC cell proliferation and apoptotic resistance. Depletion MDSCs by anti-Gr-1 monoclonal antibody in subcutaneous transplanted tumor model abrogated tumor promotion by ICC-CAFs suggested that the pro-tumor function of Fibroblastic FAP relied on MDSCs. Mechanical, flow cytometry and chamber migration assay were conducted to find Fibroblastic FAP was required by the ability of ICC-CAFs to promote MDSC migration directly. Moreover, fibroblastic FAP knockdown had no effect on cell proliferation and apoptotic resistance. Here, we revealed the T-cell independent mechanisms underlying the ICC-promoting effect of fibroblastic FAP by attracting MDSCs via CCL2, which was mainly attributed to the ability of FAP to attract MDSCs and suggests that specific targeting fibroblastic FAP may represent a promising therapeutic strategy against ICC.

• Authors: Yuli Lin, Bingji Li, Xuguang Yang, Qian Cai, Weiren Liu, Mengxin Tian, Haoyang Luo, Wei Yin, Yan Song, Yinghong Shi, Rui He
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 21 Issue 12 Pg. 1133-1142 (12 2019) ISSN: 1476-5586 [Electronic] United States
• PMID: 31759251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Ly
• Membrane Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• Animals
• Antigens, Ly (metabolism)
• Apoptosis (genetics)
• Bile Duct Neoplasms (etiology, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Cholangiocarcinoma (etiology, metabolism, pathology)
• Disease Models, Animal
• Endopeptidases
• Fibroblasts (metabolism)
• Gelatinases (genetics, metabolism)
• Gene Knockdown Techniques
• Heterografts
• Humans
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Myeloid-Derived Suppressor Cells (immunology, metabolism)
• STAT3 Transcription Factor (metabolism)
• Serine Endopeptidases (genetics, metabolism)
• Tumor Microenvironment (genetics)