神戸大学大学院医学研究科生化学・分子生物学講座シグナル統合学分野※Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine― 211 ―In this research and development, we aim to elucidate the molecular mechanism of how cancer cells survive by escaping immune surveillance, particularly by innate immune cells as macrophages (MΦ) or dendritic cells (DCs). In addition, we aim to establish an innovative cancer treatment method by controlling innate immune cells. From this study, we first found that CD47 on T cells prevents their necroptotic cell death initiated by cDCs and thereby promotes T cell survival and function. Thus, we have elucidated a novel function of CD47 essential for the survival and maintenance of T cells. We have also established a preclinical evaluation system for anti-human SIRPα antibodies by using HIS-MITRG mice, reconstituted with the human immune system, as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human tumor-associated macrophages. We will also conduct research on the application of such humanized mice to patient-personalized treatment in the future. Finally, we have found that an anti-SIRPα/β antibody provides antitumor activity against various cancers through SIRPβ and its mechanism of action by using in vitro and mouse models. We will also further develop the preclinical POC of anti-SIRPβ antibodies. Overall, this study has elucidated the molecular mechanism of how cancer cells escape immune surveillance and thereby survive in the tumor microenvironment. Moreover, the study will indeed contribute to the development of new antitumor agents and eventually to total cancer eradication in the future.※神戸大学大学院医学研究科生化学・分子生物学講座生体シグナル制御学部門AbstractStudy for the molecular mechanism of innate immune cell regulation by cancer cells and the development of a novel がん細胞による自然免疫制御の分子基盤解明と新規がん治療法開発への応用cancer therapy的崎 尚Takashi Matozaki
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