CCL2 is critical for immunosuppression to promote cancer metastasis

Chie Kudo-Saito, Hiromi Shirako, Misa Ohike, Nobuo Tsukamoto, Yutaka Kawakami

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)393-405
Number of pages13
JournalClinical and Experimental Metastasis
Volume30
Issue number4
DOIs
Publication statusPublished - 2013 Apr

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Immunosuppression
Neoplasm Metastasis
Neoplasms
Epithelial-Mesenchymal Transition
Snails
Immunosuppressive Agents
Tumor Escape
Tumor Microenvironment
Chemotactic Factors
HLA-DR Antigens
Regulatory T-Lymphocytes
Dendritic Cells
Small Interfering RNA
Epithelial Cells

Keywords

  • CCL2
  • EMT
  • Immunosuppression
  • Lipocalin 2
  • Metastasis
  • Snail

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CCL2 is critical for immunosuppression to promote cancer metastasis. / Kudo-Saito, Chie; Shirako, Hiromi; Ohike, Misa; Tsukamoto, Nobuo; Kawakami, Yutaka.

In: Clinical and Experimental Metastasis, Vol. 30, No. 4, 04.2013, p. 393-405.

Research output: Contribution to journalArticle

Kudo-Saito, Chie ; Shirako, Hiromi ; Ohike, Misa ; Tsukamoto, Nobuo ; Kawakami, Yutaka. / CCL2 is critical for immunosuppression to promote cancer metastasis. In: Clinical and Experimental Metastasis. 2013 ; Vol. 30, No. 4. pp. 393-405.
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