Abstract C31: Downregulation of IL-12 through IL-6 production increased cancer metastasis after radiotherapy

Abstract

Abstract Radiotherapy (RT) is a potent antitumor modality. However, unwanted effect is also reported such as increased metastasis through complex molecular mechanism including cytokines. Cytokines are soluble messengers that directly stimulate immune cells and stromal cells at the tumor site and enhance cancer cells recognition by immune cells. Numerous studies have investigated that cytokines have anti-tumor efficacy for cancer therapy. In this study, we investigated levels of 6 cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12 and TNF-α) in serum of before and after RT of HCC patients treated with RT and evaluate its significance in relation to clinical outcome. As a result, intrahepatic metastasis out of RT field increased in patients with IL-12 decreas after RT (p = 0.043). IL-12 is an inflammatory cytokine that induces interferon-γ production from Th1 and NK cells. IL-12 mainly produced from antigen presenting cells as dendritic cells (DCs) which against many tumors is probably the result of its stimulatory effects on cell mediated immune responses. Therefore, we investigated anti-tumor and anti-metastatic effects of mesenchymal stem cells expressing IL-12 (MSC/IL-12) treatment with ionizing radiation (IR) in murine hepatic cancer (HCa-1) model. Tumor bearing syngenic mice were treated with IR, MSC/IL-12 or combination of both. Combination of MSC/IL-12 and IR resulted in suppression of lung metastasis as well as significantly growth delay of Hca-1. Especially, expressions of CD4, CD8 and CD11C were increased in tumors of MSC/IL-12 and IR treated group compared with only IR. Also, to understand the detailed mechanism on anti-tumor effect of IL-12 in IR treated HCC, splenocyte were irradiated with 2, 5 Gy and measured IL-6 and IL-12 by ELISA after cultured. As results, IL-6 significantly increased by IR, while IL-12 increased at 1 day but it was decreased in dose dependent manner at 3days. These results indicated that IL-12 production could be mediated by IL-6 signaling. To prove that, DCs were irradiated with 5 and 10 Gy in presence or absence of LPS after differentiated from mice bone marrow and analyzed expressions of CD80 and 86 by FACS. The expression of CD80 and 86 decreased in irradiated-DCs comparing to no-irradiated DCs. Also, LPS-induced expressions of CD 80, 86 and IL-12 increased in α-IL-6 treated DCs compared with no-treated DCs. Taken together, diminishing IL-12 via IL-6 production by IR seems to increase the treatment failure after radiotherapy in hepatocellular carcinoma. Citation Format: Jinsil Seong, Eun Jung Lee, Keun Young Jeong. Downregulation of IL-12 through IL-6 production increased cancer metastasis after radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C31.