Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO
Introduction
Tumor progression is now recognized as the product of evolving crosstalk between different cell types within tumors and in the tumor-surrounding stroma. However, the mechanisms regulating this crosstalk are complicate and remain unclear. The tumor-surrounding stroma consists of extracellular matrix (ECM) and stroma cells, which are fibroblasts, various inflammatory cells, endothelial cells and pericytes, these cells are all imbedded in the ECM that is produced by fibroblasts [1], [2].
Fibroblasts are the dominant stromal cell type that is important for tumorigenesis [3], [4]. Cancer associated-fibroblasts (CAFs) have been shown to promote tumor growth by inducing angiogenesis, recruiting bone marrow derived endothelial progenitor cells, remodeling the ECM by enhancing integrin signaling through matrix crosslinking, and promoting epithelial to mesenchymal transition [5]. CAFs can even mediate tumor resistance to anti-VEGF treatment through secretion of PDGF-C [6]. Recent studies have shown that fibroblasts and APCs from the microenvironment of human lung tumors have reciprocal interactions with T cells, which result in the enhanced production of IFN-γ and IL-17A by T cells [7], [8]. These observations are in accordance with growing evidence that fibroblasts have an unexpected role in regulating immune cell function, but the exact underlying mechanisms behind this regulation in tumors are not yet clear.
NK cells constitute a major component of the innate immune system, and they kill target cells without MHC restriction or prior sensitization [9]. It has been reported that NK cell dysfunction leads to advanced disease progression in several types of human solid tumors [10], [11]. Although not directly related to cancer, NK cells can be strongly regulated by both activating and inhibitory receptors, as well as soluble factors derived from APCs or fibroblasts under inflammatory conditions. However, the precise mechanism underlying NK cell regulation in tumor microenvironments is not fully understood.
HCC is the fifth most common cancer worldwide, with an extremely poor prognosis [12], [13]. To better understand the interaction between tumor stroma cells, we set out to investigate how HCC-associated fibroblasts orchestrate NK cell function in vitro using a cell-to-cell direct interaction model, which is stereotypical of tumor stroma inflammation in the human body. The present study showed that fibroblasts derived from tumors profoundly suppressed NK cell functions through PGE2 and IDO. This suppression could be almost fully restored by PGE2 or/and IDO inhibitors. Therefore, expression of PGE2 and IDO by HCC-associated fibroblasts may represent a novel mechanism by which the antitumor activity of NK cells is modulated in tumor microenvironments.
Section snippets
Patients and specimens
Tumor samples from HCC patients and foreskin samples from healthy donors were obtained from the Third Affiliated Hospital of Sun Yat-sen University. Five untreated patients with pathologically confirmed HCC had HBV infection and a background of liver cirrhosis. Peripheral leukocytes were obtained from healthy donors attending the Guangzhou Blood Center. Samples were anonymously coded in accordance with local ethical guidelines (as stipulated by the Declaration of Helsinki), and written informed
Phenotypic characteristics of human fibroblasts from HCC and foreskin
To evaluate the potential role of fibroblasts in tumor pathogenesis, we first examined the distribution of activated fibroblasts in HCC tissues stained for α-SMA, paying particular attention to the tissue micro-localization of the cells. As shown in Fig. 1A, activated fibroblasts were present throughout the tissue but often accumulated in the tumor-surrounding stroma, which in most HCCs contains a significant amount of infiltrated leukocytes [17]. We then purified and cultured fibroblasts from
Discussion
Although cancer patients exhibit a generalized immunosuppressive status, there is substantial evidence that stromal activation can foster tumor growth and progression [20]. In the present study, we observed that fibroblasts were enriched predominantly in the tumor-surrounding stroma of HCC, which contained a significant amount of infiltrated leukocytes [17]. Most of these fibroblasts exhibited an activated phenotype, and accordingly, HCC associated fibroblasts effectively triggered in vitro
Acknowledgements
This work was supported by: State 973 National Basic Research Program of China (2009CB522404), Program for New Century Excellent Talents in University (NCET-08-0583), National Natural Science Foundation of China (NSFC-30972914), State Key Projects on Infection Diseases of China (2008ZX10002-025, 026), Training Program Foundation for Innovative Talents by Sun Yat-sen University (82000-3126202) as well as Key project of Medical Science in SYSU (10YKJC03).
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These authors contributed equally to this work.