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CCL2 is critical for immunosuppression to promote cancer metastasis

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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.

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Abbreviations

BM:

Bone marrow

CA:

Cryoablation

DC:

Dendritic cell

DCreg:

Immunoregulatory dendritic cell

EMT:

Epithelial-to-mesenchymal transition

F10-mock:

B16-F10 cells transduced with empty vector

F3-snail+ :

Panc1 cells transduced with human snail cDNA

H6-snail+ :

B16-F10 cells transduced with murine snail cDNA

i.t. (IT):

Intratumoral(ly)

LCN2:

Lipocalin 2

MDSCs:

Myeloid-derived suppressor cells

MFI:

Mean of fluorescence intensity

MSCs:

Mesenchymal stem cells

Panc1-mock:

Panc1 cells mock-transfected with empty vector

SPCs:

Spleen cells

TAMs:

Tumor-associated macrophages

Treg:

Regulatory T cells

TSP1:

Thrombospondin 1

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Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (18591484, 19390355, 19590405, and 21590445), The Sagawa Foundation for Promotion of Cancer Research, and Keio Gijuku Academic Development Funds.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

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

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  1. Chie Kudo-Saito
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  2. Hiromi Shirako
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  3. Misa Ohike
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  4. Nobuo Tsukamoto
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  5. Yutaka Kawakami
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Correspondence to Chie Kudo-Saito or Yutaka Kawakami.

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Kudo-Saito, C., Shirako, H., Ohike, M. et al. CCL2 is critical for immunosuppression to promote cancer metastasis. Clin Exp Metastasis 30, 393–405 (2013). https://doi.org/10.1007/s10585-012-9545-6

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