Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression.

Abstract:

:STAT3 is an important transcriptional factor for cell growth, differentiation, and apoptosis. Although evidence suggests a positive role for STAT3 in cancer, the inhibitory effects of tumor STAT3 on natural killer (NK) cell functions in human hepatocellular carcinoma are unclear. In this study, we found that blocking STAT3 in hepatocellular carcinoma cells enhanced NK-cell antitumor function. In the case of STAT3-blocked hepatocellular carcinoma cells, NKG2D ligands were upregulated, which promoted recognition by NK cells. Importantly, the cytokine profile of hepatocellular carcinoma cells was altered; in particular, TGF-β and interleukin 10 (IL-10) expression was reduced, and type I interferon (IFN) was induced, thus facilitating NK-cell activation. Indeed, the cytotoxicity of NK cells treated with supernatant from STAT3-blocked hepatocellular carcinoma cells was augmented, with a concomitant elevation of molecules associated with NK cytolysis. Further experiments confirmed that the recovery of NK cells depended on the downregulation of TGF-β and upregulation of type I IFN derived from STAT3-blocked hepatocellular carcinoma cells. These findings demonstrated a pivotal role for STAT3 in hepatocellular carcinoma-mediated NK-cell dysfunction, and highlighted the importance of STAT3 blockade for hepatocellular carcinoma immunotherapy, which could restore NK-cell cytotoxicity in addition to its direct influence on tumor cells.

journal_name

Mol Cancer Ther

authors

Sun X,Sui Q,Zhang C,Tian Z,Zhang J

doi

10.1158/1535-7163.MCT-12-1087

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

2885-96

issue

12

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-12-1087

journal_volume

12

pub_type

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