title: 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.affiliation: Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. kudoc@a3.keio.jp
authors.forename: Chie
authors.initials: C
authors.lastname: Kudo-Saito
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shirako
authors.forename: Misa
authors.initials: M
authors.lastname: Ohike
authors.forename: Nobuo
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007165:Immunosuppression Therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D000071250:Snail Family Transcription Factors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; C423236:CD274 protein, human; D018932:Chemokine CCL2; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors