Abstract
STAT3 is highly activated in a wide variety of cancers and functions to promote tumor survival. We previously reported that blocking STAT3 activation inhibited human hepatocellular carcinoma (HCC) growth in vitro, but whether this treatment also triggered antitumor immune responses in vivo remained unknown. In this study, we found that blocking the STAT3 pathway in HCC cells dramatically inhibited murine HCC growth in vivo and prolonged survival of tumor-bearing mice. Importantly, the presence of STAT3-blocked HCC augmented NK cell cytotoxicity against HCC and increased expression of molecules associated with NK cell activation and cytotoxicity. In T cell–deficient nude mice, a unique NK cell–mediated antitumor function against STAT3-blocked HCC was suggested. NK cells were shown to be necessary and sufficient in NK or T cell depletion experiments, or by adoptively transferring NK cells. Furthermore, regulatory T cells and immunosuppressive IL-10 and TGF-β cytokines were reduced in mice bearing STAT3-blocked HCC cells, suggesting that these factors may be involved in HCC-induced NK cell suppression. These findings indicate that blocking STAT3 in HCC cells can initiate innate immunity in vivo.
Footnotes
This work was supported by National Basic Research Program of China Grant 2013CB531503, National Natural Science Foundation of China Grants 30628014 and 81172789, and National Mega Project on Major Infectious Diseases Prevention and Treatment Grant 2012ZX10002006.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- DC
- dendritic cell
- FasL
- Fas ligand
- HCC
- hepatocellular carcinoma
- ODN
- oligonucleotide
- Treg
- regulatory T cell
- VEGF
- vascular endothelial growth factor.
- Received September 9, 2013.
- Accepted June 10, 2014.
- Copyright © 2014 by The American Association of Immunologists, Inc.