Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited effective treatment options. An alternative strategy is to target cells, such as tumor-infiltrating macrophages, in the microenvironment of liver cancers. Tumor-associated macrophages (TAMs) are believed to promote cancer initiation and malignancy and to be involved in tumor development, tumor control, and response to treatment. The CCL2/CCR2 axis is required for recruitment of monocytes/macrophages and is implicated in various aspects of liver pathology, including acute liver injury, chronic hepatitis, cirrhosis, and tumorigenesis. 

 A team of scientists led by Dr. WANG Hui from the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences found that, in two independent cohorts, CCL2 is overexpressed in human HCCs and is associated with a poor prognosis for patients. The CCL2/CCR2 signaling axis mediates cross-talk between tumor cells and stromal cells and supports the growth and metastasis of liver cancer cells. These results are consistent with the concept that the CCL2/CCR2 axis is a new therapeutic target for HCCs with overexpressed CCL2.  

Researchers found that blocking CCL2/CCR2 signaling with a novel CCR2 antagonist inhibits HCC growth and metastasis, reduces post-surgical recurrence, and enhances survival. Mechanistically, CCR2 antagonist reduces the number of peripheral blood inflammatory monocytes and tumor-infiltrated TAMs, suppresses the M2 polarization of macrophages and overcomes the immunosuppressive effect of TAMs on cytotoxic T lymphocytes. Consistent with these results, depletion of CD8⁺ T cells or T cell immune deficiency abolishes the antitumor activity of the CCR2 antagonist. The results from the present study have high potential for translation to clinical practice.  

The findings not only reveal the mechanism of CCL2/CCR2-mediated cross-talk among tumor cells, macrophages, and cytotoxic T lymphocytes in the tumor microenvironment but also identify tumor-infiltrating macrophages as a therapeutic target for HCCs and demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs. 

This work was published online in GUT on October 9, 2015, as a research article entitled "Targeting of tumor-infiltrating macrophages via CCL2/CCR2 signaling as a therapeutic strategy against hepatocellular carcinoma".  

This study was funded by Ministry of Science and Technology of China, the National Natural Science Foundation of China, Chinese Academy of Sciences and the Science and Technology Commission of Shanghai Municipality. 

CCR2 antagonist targets tumor-associated macrophages and activates an antitumoral CD8⁺ T cell response. (Image by Dr. WANG Hui’s Lab)

Contact:
WANG Hui, Ph.D., Principal Investigator
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai 200031, China.
Tel: 86-21-54920941;
Fax: 86-21-54920291;
E-mail: huiwang@sibs.ac.cn