CCL2 is critical for immunosuppression to promote cancer metastasis.

Abstract

We previously found that cancer metastasis is accelerated by immunosuppression during Snail-induced epithelial-to-mesenchymal transition (EMT). However, the molecular mechanism still remained unclear. Here, we demonstrate that CCL2 is a critical determinant for both tumor metastasis and immunosuppression induced by Snail(+) tumor cells. CCL2 is significantly upregulated in various human tumor cells accompanied by Snail expression induced by snail transduction or TGFβ treatment. The Snail(+) tumor-derived CCL2 amplifies EMT events in other cells including Snail(-) tumor cells and epithelial cells within tumor microenvironment. CCL2 secondarily induces Lipocalin 2 (LCN2) in the Snail(+) tumor cells in an autocrine manner. CCL2 and LCN2 cooperatively generate immunoregulatory dendritic cells (DCreg) having suppressive activity accompanied by lowered expression of costimulatory molecules such as HLA-DR but increased expression of immunosuppressive molecules such as PD-L1 in human PBMCs. The CCL2/LCN2-induced DCreg cells subsequently induce immunosuppressive CD4(+)FOXP3(+) Treg cells, and finally impair tumor-specific CTL induction. In murine established tumor model, however, CCL2 blockade utilizing the specific siRNA or neutralizing mAb significantly inhibits Snail(+) tumor growth and metastasis following systemic induction of anti-tumor immune responses in host. These results suggest that CCL2 is more than a chemoattractant factor that is the significant effector molecule responsible for immune evasion of Snail(+) tumor cells. CCL2 would be an attractive target for treatment to eliminate cancer cells via amelioration of tumor metastasis and immunosuppression.

• Authors: Chie Kudo-Saito, Hiromi Shirako, Misa Ohike, Nobuo Tsukamoto, Yutaka Kawakami
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 30 Issue 4 Pg. 393-405 (Apr 2013) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 23143679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CCL2 protein, human
• CD274 protein, human
• Chemokine CCL2
• RNA, Messenger
• Snail Family Transcription Factors
• Transcription Factors

Topics

• Animals
• Apoptosis
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Cell Adhesion
• Cell Movement
• Cell Proliferation
• Chemokine CCL2 (antagonists & inhibitors, genetics, metabolism)
• Chemotaxis
• Epithelial-Mesenchymal Transition
• Flow Cytometry
• Gene Expression Profiling
• Humans
• Immunosuppression Therapy
• Melanoma, Experimental (immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplasm Metastasis
• Oligonucleotide Array Sequence Analysis
• Pancreatic Neoplasms (immunology, metabolism, pathology)
• RNA, Messenger (genetics)
• Snail Family Transcription Factors
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured