Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells

Hepatology. 2010 Jan;51(1):154-64. doi: 10.1002/hep.23291.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / pathology
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Humans
  • Interleukin-17 / biosynthesis*
  • Interleukin-1beta / physiology
  • Interleukin-23 / physiology
  • Interleukin-6 / physiology
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Mice
  • Monocytes / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*


  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-23
  • Interleukin-6