Abstract 4079: IL-6 promotes radiation-induced macrophage infiltration to tumors via upregulation of CCL2 and CCL5
Authors: Wang Xin , Tsai Ying , Chuang Kwang-Hsiang , Keng Peter , Lee Soo Ok , Chen Yuhchyau 
Published: July 2016

Abstract
Background: Radiotherapy is a major treatment modality for non-small cell lung cancer (NSCLC), and it is controversial if radiotherapy contributes to metastasis. We hypothesize that radiotherapy increases lung cancer cell recruitment of macrophage-infiltration, and the infiltrated macrophages may accelerate the metastatic potential of cancer. We examined the role of intracellular IL-6 in NSCLC cells in promoting the recruitment of macrophages after irradiation and explored the molecular mechanisms that govern the increase of macrophages.
Methods: By utilizing the IL-6 knocked down (IL-6si) and scramble control (sc) A549 and H157 NSCLC cell lines, we investigated whether the intracellular IL-6 level affected macrophage migration into cancer cells. We also developed orthotopic human xenograft models in nude mice using the luciferase tagged-H157IL-6si and H157sc cells and investigated IL-6 effects on macrophage infiltration to tumor sites after irradiation. Tumors were irradiated and the irradiated mice were divided into two groups: (1) 1st group, the endogenous macrophage-infiltration into tumors was examined; and (2) in the 2nd group, mice were injected with the GFP-labeled THP-1 cells through tail veins after irradiation, and the recruitment of exogenous macrophages (THP-1) to tumor site was investigated 3 days after the injection. We also studied the molecular mechanisms by which IL-6 mediated the increase of macrophage-infiltration upon irradiation.
Results: We found a decrease of macrophage recruitment by A549/H157 cells upon radiation when IL-6 was knocked down. Consistent with the in vitro results, we observed the contribution of IL-6 signaling to promote macrophage-infiltration after irradiation in vivo in human tumor xenografts. In the mechanism dissection studies, we found that CCL2 and CCL5 molecules were the critical IL-6 downstream target molecules, which mediated the radiation-induced increase of macrophage infiltration. We confirmed the contribution of these molecules by demonstrating the effects of neutralizing antibodies to these target molecules in reducing the radiation-induced enhancement of macrophage migration to tumors.
Conclusion and Impacts: Study results suggest that IL-6 signaling, through the up-regulation of CCL2/CCL5, mediated the increase of macrophage infiltration to NSCLC cells after irradiation. Molecular studies suggest that blocking CCL2/CCL5 pathways can potentially be applied to conventional radiotherapy to intercept the process of radiation-promoted macrophage-infiltration.
Citation Format: Xin Wang, Ying Tsai, Kwang-Hsiang Chuang, Peter Keng, Soo Ok Lee, Yuhchyau Chen. IL-6 promotes radiation-induced macrophage infiltration to tumors via upregulation of CCL2 and CCL5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4079.