Abstract
Radiotherapy (RT) is a potent anti-tumor modality. However, unwanted effects including increased recurrence and metastasis that involve factors such as cytokines, which induce complex molecular mechanisms, have also been reported. In a previous study, we showed that interleukin (IL)-12 and radiotherapy combination treatment suppressed tumor growth and metastasis in a hepatoma mouse model. In this study, we investigated the mechanism underlying the IL-12 anti-tumor effect during radiotherapy. In tumor-bearing mice, irradiation decreased IL-12 expression in the tumors and spleens. However, a number of dendritic cells infiltrated into the tumors in which IL-12 expression did not decrease. To further study the underlying detailed mechanism for this decrease in IL-12, LPS-stimulated bone marrow–derived dendritic cells (BMDCs) were irradiated, and then IL-12– and IL-6–associated molecules were examined in irradiated tumors and BMDCs. Irradiation resulted in IL-12 suppression and IL-6 increase. IL-6 and signal transducer and activator of transcription 3 (STAT3) inhibitors restored the irradiation-induced IL-12 decrease via suppression of C-Rel activation. Taken together, our study suggests that irradiation-induced IL-6 can decrease IL-12 production through the inhibition of C-Rel phosphorylation by the IL-6/STAT3 signaling pathway.
Highlights
Radiation (RT) is a potent anti-tumor modality used to treat various cancers, including glioma, breast, colon, lung, liver, head, and neck cancers
To investigate possible tumor-derived soluble factors induced by irradiation that contributed to the decrease of IL-12 in dendritic cells (DCs), DCs were isolated from mouse bone marrow cells (BMDCs) that were differentiated in media containing IL-4 (10 ng/mL) and granulocyte macrophage colony-stimulating factor (GM-CSF) (10 ng/mL) for 6 days and these were incubated for 72 h in supernatants of MIH-2 cell irradiated with or without 10 Gy
Many previous studies suggest that radiotherapy can lead to immunogenic cell death via recruitment of immune cells such as DCs, macrophages, and lymphocytes into the tumors by the release of radiation-induced damage-associated molecular patterns (DAMPs) including high-mobility group protein B1 (HMGB1), HSP, and calreticulin [34, 35]
Summary
Radiation (RT) is a potent anti-tumor modality used to treat various cancers, including glioma, breast, colon, lung, liver, head, and neck cancers. The main mechanisms involved in STAT3 activation are IL-6 autocrine synthesis and IL-6 paracrine activation from the stroma and infiltrating inflammatory-associated immune cells [15]. STAT3 expression in the tumor microenvironment can modulate IL-12 and IL-23 secretion by immune cells such as dendritic cells (DCs) and macrophages [16]. We previously reported the anti-tumor effect of RT combination treatment and IL-12 expressed through both mesenchymal stem cells and armed oncolytic adenovirus in a murine hepatic cancer model [20, 21]. The present study was designed to demonstrate the underlying mechanism of the IL-12/RT combination treatment and IL-12 regulation in DCs by radiation
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