Activated Monocytes in Peritumoral Stroma of Hepatocellular ... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Activated Monocytes in Peritumoral Stroma of Hepatocellular Carcinoma Promote Expansion of Memory T Helper 17 Cells

Kuang, Dong-Ming1,2; Peng, Chen2; Zhao, Qiyi2; Wu, Yan2; Chen, Min-Shan1; Zheng, Limin1,2,*

1_State Key Laboratory of Oncology in Southern China, Cancer Center, Guangzhou, P.R. China_

2_State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China_

*Address reprint requests to: School of Life Sciences, Sun Yat-Sen University, Guangzhou 510 275, P.R. China. Email:[email protected]; fax: 86-20-84112169

Received 12 April 2009; Accepted 12 August 2009

Published online 9 September 2009 in Wiley InterScience (www.interscience.wiley.com).

Supported by the Outstanding Young Scientist Fund and project grants from the NSFC, China (30425025 and 30730086), the “973” Program (2004CB518801 and 2010CB529904), and the Ministry of Health of P.R. China (2008ZX10002-019).

Potential conflict of interest: Nothing to report.

Additional Supporting Information may be found in the online version of this article.

Abstract

Although cancer patients exhibit a generalized immunosuppressive status, substantial evidence indicates that the inflammatory reaction at a tumor site can promote tumor growth and progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. We recently found that proinflammatory T helper (Th)17 cells are accumulated in HCC tissue, where they promote disease progression by fostering angiogenesis. Here we show that interleukin (IL)-17-producing cells were enriched predominantly in peritumoral stroma of HCC tissues, and their levels were well correlated with monocyte/macrophage density in the same area. Most peritumoral CD68+ cells exhibited an activated phenotype. Accordingly, tumor-activated monocytes were significantly superior to the suppressive tumor macrophages in inducing expansion of Th17 cells from circulating memory T cells in vitro with phenotypic features similar to those isolated from HCCs. Moreover, we found that tumor-activated monocytes secreted a set of key proinflammatory cytokines that triggered proliferation of functional Th17 cells. Inhibition of monocytes/macrophages inflammation in liver markedly reduced the level of tumor-infiltrating Th17 cells and tumor growth in vivo . Conclusion: The proinflammatory Th17 cells are generated and regulated by a fine-tuned collaborative action between different types of immune cells in distinct HCC microenvironments, and allows the inflammatory response of activated monocytes to be rerouted in a tumor-promoting direction. Selectively modulating the “context” of inflammatory response in tumors might provide a novel strategy for anticancer therapy. (Hepatology 2009.)