Chemical augmentation of mitochondrial electron transport chains tunes T-cell activation threshold in tumors 2

• Material Type: 博士論文
• ISSN: 2051-1426
• Title: Chemical augmentation of mitochondrial electron transport chains tunes T-cell activation threshold in tumors
• Volume: 10 2
• Author/Editor: 道津, 洋介
• Author Heading: 道津, 洋介
• Publication, Distribution, etc.: BMJ
• Publication Date: 2022-03-18
• Publication Date (W3CDTF): 2022-03-18
• Alternative Title: 電子伝達系を介したミトコンドリアの活性化を誘導する新規代謝化合物は、腫瘍局所におけるT細胞の抗原認識能を向上し、抗腫瘍効果に寄与する
• Periodical title: Journal for ImmunoTherapy of Cancer
• Degree grantor/type: Nagasaki University (長崎大学)
• Date Granted: 2022-03-18
• Date Granted (W3CDTF): 2022-03-18
• Dissertation Number: 甲医歯薬第1425号
• Degree Type: 博士(医学)
• Conferring No. (Dissertation): 甲医歯薬第1425号
• Text Language Code: eng
• Target Audience: 一般
• Note (General): Background: Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvironment. Thus, augmenting TCR-mediated recognition of tumor antigens is a useful strategy to improve the efficacy of cancer immunotherapy.Methods: We screened 310 small molecules from our library and identified PQDN, a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. We used inhibitors of mitochondrial functions and Seahorse Flux Analyzer to investigate the mechanism underlying the effect of PQDN on T cells. Effect of PQDN on tumor-infiltrating CD8 T cells was examined using flow cytometry and TCR repertoire analysis.Results: PQDN increased mitochondrial reciprocal capacity through enhancement of electron transport chains (ETCs) and facilitated glycolysis via mTOR/AKT signaling, resulting in augmented CD8 T cell activation, even when antigen stimulation is extremely weak. Intratumoral administration of this compound into tumor-bearing mice tunes inactivated T cell with tumor antigen recognition potent and expanded functional T cell receptor diversity of tumor-infiltrating T cells, augmenting antitumor immune responses and retarding tumor growth. Furthermore, PQDN has a synergistic potent with T cell dependent immunotherapy, such as checkpoint inhibitory therapy or adoptive cell therapy, even in a low immunogenic tumor. We also demonstrated that this compound enhances the activation of human CD8 T cells.Conclusions: These data suggest that tuning the T cell activation threshold by chemical activation of mitochondrial ETC is a new strategy for improving therapeutic efficacy through the activation of low-avidity tumor-specific T cells.; 長崎大学学位論文 学位記番号:博(医歯薬)甲第1425号 学位授与年月日:令和4年3月18日; Author: Yosuke Dotsu, Daisuke Muraoka, Naohisa Ogo, Yudai Sonoda, Kiyoshi Yasui, Hiroyuki Yamaguchi, Hideo Yagita, Hiroshi Mukae, Akira Asai and Hiroaki Ikeda; Citation: Journal for ImmunoTherapy of Cancer, 10(2), art.no. e003958; 2022; identifier:Nagasaki University (長崎大学), 博士(医学) (2022-03-18); http://hdl.handle.net/10069/00041428
• DOI: info:doi/10.1136/jitc-2021-003958; https://doi.org/info:doi/10.1136/jitc-2021-003958
• Persistent ID (NDL): info:ndljp/pid/12296820; https://dl.ndl.go.jp/pid/12296820
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2022-06-05T18:01:14+09:00
• Date Created (W3CDTF): 2022-05-18
• Format (IMT): PDF
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Related Material (URI): http://hdl.handle.net/10069/00041428
• Periodical Title (URI): http://hdl.handle.net/10069/00041534
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp