LAUSR

Abstract: Release and presentation of tumor antigens are the preconditions of cellular immune response. Radiotherapy have been reported to release endogenous tumor antigens and enhanced the adjuvanticity from dying cancer cells via endoplasmic reticulum (ER) stress, known as immunogenic cell death. We developed a novel radiotherapy using radiosensitizer (TiOxNPs) that could drive effective anti-tumor responses. The TiOxNPs were robustly radiation-induced reactive oxygen species (ROS) generation. This burst therapy could enhance to release and presentation of endogenous tumor antigens, subsequently cross-presentation of antigens by Dendritic cells (DCs) for T-cell activation in secondary lymphoid organs (SLO). Methods: B16-F10 murine melanoma cells (5 × 105) were subcutaneously injected into the right flank of C57BL/6J respectively. Mice were divided into five treatment groups: 1) untreated; 2) XRT; 3) XRT+ TiOxNPs; 4) XRT+anti-PD-1Ab; and 5) XRT+ TiOxNPs +anti-PD-1Ab. B16-F10 tumors were intratumorally injected with TiOxNPs (8mg/kg) on days 10 and received 5Gy or 10Gy X-ray radiation approximately 1 hour after the injection. Anti-PD-1 antibody (200µg) intraperitoneally administered to the mice on the first day of X-ray irradiation, days 13 and 16. The tumor volume were assessed every 2-3 days after treatment. Mice were sacrificed after days 17 and isolated spleen and tumor. Results: TiOxNPs acted as a potent radiosensitizer, which enhanced cytotoxic ROS-mediated cell death. This combination effect could not only a local treatment that directly kills cancer cells but also could enhance the adjuvanticity from dying cancer cells by DAMPs, and significantly upregulate expression of MHC class I on tumor cells. Treatment of B16-F10 melanoma tumor model with burst therapy resulted in tumor shrinkage and extended overall survival. Burst therapy facilitated the recruitment and maturation of DCs into SLO, and improved antigen presentation to naive T cells. Infiltration into the tumor site of CTL were correlated with increasing of migration DCs into SLO. Conclusion: A novel radiotherapy combining with TiOxNPs played an important role in release of endogenous tumor antigens and DAMPs. The upregulation of MHC class I expression on tumor cells after X-ray irradiation facilitated the recognition of the tumor cells by T cells, leading to significantly enhanced antitumor immune response compared to exisiting immunoradiotherapy. This novel nanoparticles exposed to X-ray irradiation could trigger of antigen-specific immune responses and transform a tumor into a site for activation of antitumor immune response. Citation Format: Yoshiko Fujita, Hikaru Kubota, Chiaki Ogino, Ryohei Sasaki. Anti-tumor immunity evolved by novel titanium peroxide nanoparticles (TiOxNPs) as a radiosensitizer and PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6408.