Abstract 773: Inhibition of HIF-1 impairs TGF-β-mediated immunosuppression

Abstract

Abstract Hypoxia is one of distinctive features of the tumor microenvironment. In the tumor tissues under hypoxia, a transcription factor, hypoxia-inducible factor-1 (HIF-1) plays a critical role in regulating expressions of various genes associated with tumor growth. In order to understand the immunobiology of hypoxic tumor microenvironment, it is of great interest to elucidate the anti-tumor immune responses regulated by HIF-1. From these viewpoints, we focused on a relationship between HIF-1 and transforming growth factor-beta (TGF-β). TGF-β which is derived from either tumor cells or tumor stromal cells may be regulated by HIF-1 and suppress anti-tumor immune responses in tumor-bearing hosts. In this report, we hypothesized that eliminated expression of TGF-β by inhibition of HIF-1 in tumor tissue would contribute to augmentation of anti-tumor immune responses. We examined the possibilities in tumor-bearing mice models. C57BL/6 mice bearing mouse lymphoma E.G7 were administrated HIF-1 siRNA into the tumor tissue four times at 2-day interval. Seven days after the last administration of HIF-1 siRNA, anti-tumor immune responses elicited in the mice were examined. As results, inhibition of HIF-1 in tumor tissue led to low expression of TGF-β mRNA as well as low level of TGF-β protein there. In tumor-draining lymph nodes where TGF-β derived from tumor tissue would affect anti-tumor immune responses, the numbers of CD4+CD25+Foxp3+ cells (regulatory T cells) as well as CD11b+Gr-1+ cells (myeloid-derived suppressor cells) were decreased. Meanwhile, tumor antigen-specific CD8+ as well as CD4+ cells producing IFN-γ were increased. In spleen, production of reactive oxygen species by CD11b+Gr-1+ cells was recovered to the same level as that from normal mouse. Tumor antigen-specific CD8+ as well as CD4+ cells producing IFN-γ were increased and cytotoxic activity against target E.G7 cells were enhanced in spleen. Subsequently, tumor growth was effectively suppressed by inhibition of HIF-1. Inhibition of HIF-1 in tumor tissue can reduce expression of TGF-β there. This contributes to weakening suppressor cells in tumor-draining lymph nodes, which elicits enhanced anti-tumor immune responses systemically. These results demonstrate that hypoxia and immunosuppression in tumor microenvironment are linked by HIF-1and TGF-β, respectively. Inhibition of HIF-1 can improve anti-tumor immune responses, and provides a new rationale with the cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 773. doi:10.1158/1538-7445.AM2011-773