title: CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function.
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.
authors.affiliation: Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Chun
authors.affiliation: Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Lavoie
authors.affiliation: Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Monia
authors.initials: M
authors.lastname: Michaud
authors.affiliation: Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Carey Ann
authors.initials: CA
authors.lastname: Gallini
authors.affiliation: Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Soucy
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Odze
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Miraca Life Sciences, Newton, MA 02464, USA.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.affiliation: 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.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000150:complications / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics; D000098815:T-bet Transcription Factor
chemical_list: D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D017382:Reactive Oxygen Species; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050796:STAT3 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor