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

• Published in: Cell reports (Cambridge) Vol. 12; no. 2; pp. 244 - 257
• Main Authors: Chun, Eunyoung, Lavoie, Sydney, Michaud, Monia, Gallini, Carey Ann, Kim, Jason, Soucy, Genevieve, Odze, Robert, Glickman, Jonathan N., Garrett, Wendy S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.07.2015; Elsevier
• Subjects: Adenocarcinoma - etiology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Transformation, Neoplastic; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Colitis - complications; Colitis - pathology; Colonic Neoplasms - etiology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Disease Models, Animal; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Gene Expression Regulation; Humans; Mice; Mice, Inbred BALB C; Mice, Knockout; Myeloid Cells - cytology; Myeloid Cells - metabolism; Neutrophils - cytology; Neutrophils - metabolism; Reactive Oxygen Species - metabolism; Receptors, Antigen, T-Cell, gamma-delta - metabolism; RNA Interference; STAT3 Transcription Factor - metabolism; T-Box Domain Proteins - deficiency; T-Box Domain Proteins - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.06.024

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. [Display omitted] •CCL2 is elevated in human dysplastic colon lesions, adenoma, and adenocarcinoma•CCL2 affects MDSC accumulation and function in colonic carcinogenesis•CCL2 modulates T cell suppression of PMN-MDSCs in a STAT3-mediated fashion•CCL2 neutralization re-shapes the tumor microenvironment, halting colon cancer Chun et al. have found that CCL2 promotes colorectal carcinogenesis by influencing MDSC accumulation and function and shaping a tumor-permissive tissue microenvironment. This works suggests that CCL2 and MDSCs represent effective therapeutic targets for colon cancer prevention and interception.