Abstract 1905: Inhibition of hypoxia-inducible factor 1 (HIF-1) in tumor can augment anti-tumor immune responses in tumor-bearing mouse through suppression of transforming growth factor-beta (TGF-β)

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 points of view, we focused on a relationship between HIF-1 and an immunosuppressive cytokine, transforming growth factor-beta (TGF-β) in the tumor. TGF-β which is derived from either tumor cells or tumor stromal cells has been reported to suppress anti-tumor immune responses in tumor-bearing hosts. In this report, we hypothesized that inhibition of HIF-1 would eliminate expression of TGF-β in tumor tissue and decreased level of TGF-β would contribute to augmentation of anti-tumor immune responses. We examined the possibilities in tumor-bearing mice models. C57BL/6 mice were inoculated subqutaneously with syngeneic Lewis lung carcinoma cell LLC. Five days after tumor inoculation, mice were administrated HIF-1 siRNA into the established tumor twice at 2-day interval. Three to 7 days after the last administration of HIF-1 siRNA, anti-tumor immune responses elicited in the mice were examined. As results, HIF-1 siRNA into the established tumor contributed to low expression of TGF-β mRNA as well as low level of TGF-β protein. In the tumor-draining lymph nodes, tumor antigen-specific CD8+ cells producing IFN-γ were increased and CD4+CD25+Foxp3+ (Treg) cells were decreased by administration of HIF-1 siRNA. Enhancement anti-tumor immune responses were associated with antigen-specific cytotoxic activity in spleen. Subsequently, tumor growth was effectively suppressed in mice administrated HIF-1 siRNA. Inhibition of HIF-1 in the tumor can eliminate expression of TGF-β there, and anti-tumor immune responses are augmented through eliminated TGF-β-mediated immunosuppression. These results demonstrate that hypoxia in the tumor tissue is associated with TGF-β-mediated immunosuppression and HIF-1 inhibitors can improve anti-tumor immune responses in tumor-bearing hosts. Our mouse models provide a new rationale with the molecular-targeting therapy for HIF-1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1905.