Thus, our results indicate that macrophages are an important PLX4032 manufacturer component of the bone marrow stromal cells and may contribute to myeloma cell survival and resistance to chemotherapeutic treatment in vivo. O79 Blockade of TNFα Signaling in Tumor-associated Macrophages: a New Radiosensitizing Strategy Yuru Meng1, Michael A. Beckett1, Hua Liang1, Nico

van Rooijen2, Helena J. Mauceri1, Kenneth Cohen3, Ralph R. Weichselbaum 1 1 Department of Radiation and Cellular Oncology, The University of Chicago Medical Center, Chicago, IL, USA, 2 Department of Molecular Cell Biology, Vrije Universiteit, VUMC, Amsterdam, Netherlands, 3 Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medical Center, Chicago, IL, USA Radiotherapy is an important anti-cancer treatment and approximately 60% of all cancer patients receive radiotherapy during the course of their disease. However, improvements in the therapeutic index of radiation therapy have been mostly based on physical improvements in radiation delivery. Radiosensitizer development targeting tumor cells has not yielded effective agents. Recent investigations in several

BGJ398 laboratories have focused on the tumor stroma as a potential target for radiosensitization. Here we report that depletion of tumor associated macrophages prior to radiotherapy increases the anti-tumor effects of ionizing radiation (IR) following both systemic and local injection of macrophage depleting Liposomal Clodronate Glutamate dehydrogenase (Lip-Clod). These anti-tumor effects were noted following large single dose (20 Gy) and low dose (2 Gy) fractionated radiation. Co-implantation of tumor cells with BM-derived macrophages (BMDMφ) resulted in increased tumor resistance to IR. Experiments using animals with germ line deletions of TNF receptors 1,2 (TNFR1,2-/-) or TNFα (TNF-/-) demonstrated that the radioprotective effect of BMDMφ required intact TNFα signaling.

The radioprotective effect of TNFα was mediated by the upregulation of VEGF production in tumor associated macrophages (TAMφ). Treatment of experimental tumors with a neutralizing antibody to TNFα (EnbrelR) improved tumor regression with IR compared to IR alone without an increase in host toxicity. These data provide a mechanistic basis for targeting macrophage populations generally and TNFα induced macrophage VEGF specifically to improve radiotherapy outcomes. Y.M., M.A.B., and R.R.W. contributed equally to this work. O80 The Role of Microenvironment on the Regulation of Epstein-Barr Virus Latent Gene Expression Eva Klein 1 , Lorand L. Kis1, Daniel Salamon1 1 Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden Depending on the differentiation of EBV-carrying cells, the virally encoded proteins are expressed in various combinations. These determine the fate of the viral genome harbouring cells.