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

Abstract

Summary 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.

LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma

“…CCL2 could mediate recruitment of MDSCs to tumors and promote the function of MDSCs via STAT3 pathway. 44 And chemokine CXCL1, activated by IL-6, is also responsible for MDSCs accumulation. 45 Also, CCL2 and CXCL1 regulate the polarization of M1 macrophages to M2 phenotype and the recruitment of TAMs to tumor microenvironment.…”

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

“…We found that stimulation of TLR7 expressed by adenocarcinoma cells modulated the immune infiltrate, leading to a significant expansion in MDSCs, associated with an increased secretion of CCL2 and GM-CSF in the tumor microenvironment. Both these cytokines are known to play a key role in the recruitment of MDSCs 38,41,42 . Indeed, the absence of CCL2 production by cancer cells considerably reduces the recruitment of MDSCs into tumors 42 .…”

“…Both these cytokines are known to play a key role in the recruitment of MDSCs 38,41,42 . Indeed, the absence of CCL2 production by cancer cells considerably reduces the recruitment of MDSCs into tumors 42 .…”

Myeloid-derived suppressor cell accumulation in renal cell carcinoma is correlated with CCL2, IL-17 and IL-18 expression in blood and tumors

“…Constitutive deletion or antibody-mediated neutralization of CCL2 halts neoplastic progression in an inflammationassociated tumor model. 20,29 Interleukin-17 is a pro-inflammatory cytokine that is thought to promote neutrophil chemotaxis and degranulation, and increased expression of IL-17 has been shown in cancer cells and TAMs, suggesting it may play an important role in the regulation of the tumor microenvironment. Previous studies have suggested a causal relationship between IL-17 production and the level of circulating MDSC.…”