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


CONCLUSIONS
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.
Kuang
Dong-Ming
DM
State Key Laboratory of Oncology in Southern China, Cancer Center, Guangzhou, P.R. China.
Peng
Chen
C
Zhao
Qiyi
Q
Wu
Yan
Y
Chen
Min-Shan
MS
Zheng
Limin
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000502:physiology; D053759:Interleukin-23 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6