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.