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

被引：390

作者：

Chun, Eunyoung ^{[1
,2
]}

Lavoie, Sydney ^{[1
,2
]}

Michaud, Monia ^{[1
,2
]}

Gallini, Carey Ann ^{[1
,2
]}

Kim, Jason ^{[1
,2
]}

Soucy, Genevieve ^{[3
,4
]}

Odze, Robert ^{[3
,4
]}

Glickman, Jonathan N. ^{[3
,5
]}

Garrett, Wendy S. ^{[1
,2
,4
,6
,7
]}

机构：

[1] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[2] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Boston, MA 02115 USA

[5] Miraca Life Sci, Newton, MA 02464 USA

[6] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[7] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

来源：

CELL REPORTS | 2015年 / 12卷 / 02期

关键词：

T-BET DEFICIENCY; INTESTINAL TUMORIGENESIS; CANCER; COLON; MACROPHAGE; CARCINOMA; BLOCKADE; COLITIS; INFLAMMATION; METASTASIS;

D O I：

10.1016/j.celrep.2015.06.024

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：244 / 257

页数：14

共 63 条

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