ESTRO 2021 Abstract Book

S336

ESTRO 2021

efficacy-oriented data suggest that the potent supra-additive effect of the novel combined treatment modality is in part due to abrogation of the ADAM17-mediated, IR-induced protective effect on the tumor vasculature.

PH-0436 Comprehensive screening for drugs that modify radiation-induced immune responses M. Okumura 1,2 , J. Du 3 , S. Kageyama 1 , R. Yamashita 3 , A. Motegi 1 , H. Hojo 1 , M. Nakamura 1 , Y. Hirano 1 , Y. Okuma 4 , H.S. Okuma 5 , K. Tsuchihara 3 , A. Tetsuo 1 1 National Cancer Center Hospital East, Radiation Oncology, Kashiwa, Japan; 2 Nagoya University Graduate School of Medicine, Radiology, Nagoya, Japan; 3 National Cancer Center, Exploratory Oncology Research and Clinical Trial Center, Translational Informatics, Tokyo, Japan; 4 National Cancer Center Hospital, Thoracic Oncology, Tokyo, Japan; 5 National Cancer Center Hospital, Breast and Medical Oncology, Tokyo, Japan Purpose or Objective The efficacy of combination of radiotherapy and immune checkpoint inhibitors has recently been investigated in clinical trials. However, mutual interaction between radiation and combined drugs including chemotherapeutic drugs and its underlining mechanisms are not well understood. Therefore, the purpose of this study was to investigate the effect of clinically approved chemotherapeutic drugs or other agents on radiation-induced immune responses (RIIR) and explore the underlying mechanisms. Materials and Methods Figure 1 shows the outline of current experiments. We established a high-throughput system (HTS) using reporter gene assays for evaluating RIIR, focusing on IRFs and NFκB acting downstream of the STING pathway, which is considered a master regulator of the cancer immune reaction in the tumor microenvironment triggered by irradiation. The effects of 2,595 drugs, including drugs approved by the Food and Drug Administration (FDA), on the RIIR were quantitated.

Figure 1

Results The results of reporter gene assay well correlated with changes in the expression of immune response proteins such as programmed death-ligand 1. In the drug screening, suppression of RIIR by negative control (corticosteroid) and activation of RIIR by positive control (olaparib) were observed, and HTS was considered valid. At a drug concentration of 10 μM, 491 (19%) of 2,595 FDA-approved drugs activated RIIR, while 396 (15%) drugs suppressed RIIR by less than half, compared to irradiation alone. For detailed profiling, 233 drugs including anticancer drugs were administered at concentrations of 0.1-10μM and RIIR were assessed. Notably, inhibition of microtubule polymerization suppressed RIIR, whereas a depolymerization inhibitor activated or maintained RIIR. Micronucleus formation, which triggers the STING-type I interferon pathway, was suppressed by cell cycle inhibitors that target the cell cycle before metaphase, thereby causing suppression of RIIR. Conclusion Our study would provide an encyclopedic catalog of clinically approved drugs based on the effect of RIIR, which could form the biological basis for further clinical trials of combining radiotherapy with immunotherapies. PH-0437 Heart base irradiation causes functional changes in the conduction system: a pre-clinical model G. Walls 1 , M. Ghita 1 , K. Edgar 2 , E. Gill 2 , A. Cole 1 , S. Jain 1 , L. Overman 3 , R. Queen 4 , S. Lisgo 5 , C. Watson 2 , D. Grieve 2 , K. Williams 6 , A. McWilliam 7 , M. van Herk 7 , K. Butterworth 1 1 Queen's University Belfast, Patrick G Johnston Centre for Cancer Research, Northern Ireland, United Kingdom; 2 Queen's University Belfast, Wellcome-Wolfson Institute for Experimental Medicine, Northern Ireland, United Kingdom; 3 University of Newcastle upon Tyne, Institute of Human Genetics , England, United Kingdom; 4 University of Newcastle upon Tyne , Biosciences Institute, England, United Kingdom; 5 University of