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Cell Rep. 2015 Jul 14;12(2):244-57. doi: 10.1016/j.celrep.2015.06.024. Epub 2015 Jul 2.

CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function.

Author information

1
Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
2
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Miraca Life Sciences, Newton, MA 02464, USA.
4
Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: wgarrett@hsph.harvard.edu.

Abstract

Our study reveals a non-canonical role for CCL2 in modulating non-macrophage, myeloid-derived suppressor cells (MDSCs) and shaping a tumor-permissive microenvironment during colon cancer development. We found that intratumoral CCL2 levels increased in patients with colitis-associated colorectal cancer (CRC), adenocarcinomas, and adenomas. Deletion of CCL2 blocked progression from dysplasia to adenocarcinoma and reduced the number of colonic MDSCs in a spontaneous mouse model of colitis-associated CRC. In a transplantable mouse model of adenocarcinoma and an APC-driven adenoma model, CCL2 fostered MDSC accumulation in evolving colonic tumors and enhanced polymorphonuclear (PMN)-MDSC immunosuppressive features. Mechanistically, CCL2 regulated T cell suppression of PMN-MDSCs in a STAT3-mediated manner. Furthermore, CCL2 neutralization decreased tumor numbers and MDSC accumulation and function. Collectively, our experiments support that perturbing CCL2 and targeting MDSCs may afford therapeutic opportunities for colon cancer interception and prevention.

PMID:
26146082
PMCID:
PMC4620029
DOI:
10.1016/j.celrep.2015.06.024
[Indexed for MEDLINE]
Free PMC Article

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