Abstract
CCL5 is a member of the CC chemokine family expressed in a wide array of immune and non-immune cells in response to stress signals. CCL5 expression correlates with advanced human breast cancer. However, its functional significance and mode of action have not been established. Here, we show that CCL5-deficient mice are resistant to highly aggressive, triple-negative mammary tumor growth. Hematopoietic CCL5 is dominant in this phenotype. The absence of hematopoietic CCL5 causes aberrant generation of CD11b+/Gr-1+, myeloid-derived suppressor cells (MDSCs) in the bone marrow in response to tumor growth by accumulating Ly6Chi and Ly6G+ MDSCs with impaired capacity to suppress cytotoxicity of CD8+ T cells. These properties of CCL5 are observed in both orthotopic and spontaneous mammary tumors. Antibody-mediated systemic blockade of CCL5 inhibits tumor progression and enhances the efficacy of therapeutic vaccination against non-immunogenic tumors. CCL5 also helps maintain the immunosuppressive capacity of human MDSCs. Our study uncovers a novel, chemokine-independent activity of the hematopoietically derived CCL5 that promotes mammary tumor progression via generating MDSCs in the bone marrow in cooperation with tumor-derived colony-stimulating factors. The study sheds considerable light on the interplay between the hematopoietic compartment and tumor niche. Because of the apparent dispensable nature of this molecule in normal physiology, CCL5 may represent an excellent therapeutic target in immunotherapy for breast cancer as well as a broad range of solid tumors that have significant amounts of MDSC infiltration.
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Acknowledgements
This work was supported by a Susan G Komen Breast Cancer Foundation award (KG091243) to X M, and NIH grant (CA124820) to Y L.
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Supplementary information
Supplementary information, Figure S1
Efficiency of knock-down of CCL5 in 4T1 stable cell lines. (PDF 189 kb)
Supplementary information, Figure S2
Confirmation of bone marrow chimerism. (PDF 100 kb)
Supplementary information, Figure S3
Lung metastasis of bone marrow chimerism. (PDF 65 kb)
Supplementary information, Figure S4
Quantification of TAMs in tumor-bearing mice. (PDF 49 kb)
Supplementary information, Figure S5
Isolation of MO- and PMN-MDSCs. (PDF 196 kb)
Supplementary information, Figure S6
Quantification of CD31 expression in MDSC subsets. (PDF 40 kb)
Supplementary information, Figure S7
Production of NO and relative mRNA expression level of iNOS in different MDSC subsets. (PDF 94 kb)
Supplementary information, Figure S8
Measurement of MDSCs in early and late stages of 4T1 tumor growth. (PDF 68 kb)
Supplementary information, Figure S9
Measurement of CCL5 protein in early and late stages of 4T1 tumor growth. (PDF 24 kb)
Supplementary information, Figure S10
CD11b+ cells in spleens of DA3-tumor bearing WT and CCL5 KO mice. (PDF 153 kb)
Supplementary information, Figure S11
Bone marrow of tumor-free WT and CCL5 KO mice. (PDF 176 kb)
Supplementary information, Figure S12
Reciprocal bone marrow transplantation. (PDF 134 kb)
Supplementary information, Figure S13
In vitro cell growth of 4T1 and 4T1-GM/M. (PDF 67 kb)
Supplementary information, Table S1
Concentration of GM-CSF, M-CSF and G-CSF in murine serum (PDF 9 kb)
Supplementary information, Table S2
Concentration of GM-CSF, M-CSF and G-CSF in 4T1 stable cells (PDF 8 kb)
Supplementary information, Data S1
Materials and Methods (PDF 17 kb)
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Zhang, Y., Lv, D., Kim, HJ. et al. A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res 23, 394–408 (2013). https://doi.org/10.1038/cr.2012.178
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DOI: https://doi.org/10.1038/cr.2012.178
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