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ID 113351
タイトル別表記
PD-1はCD27およびGITRを介した共刺激存在下でもT細胞活性化を効率的に抑制する
著者
水野, 玲奈 徳島大学大学院医科学教育部(医学専攻)
Shimizu, Kenji Tokushima University
Watada, Mizuki Tokushima University
キーワード
PD-1
CD27
GITR
T cell activation
Co-receptor
TNF receptor super family
資料タイプ
学位論文
抄録
Cancer immunotherapies targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 revolutionized cancer treatment and instigated various trials to develop new cancer immunotherapies with higher therapeutic efficacy. Agonistic Abs against tumor necrosis factor receptor super family (TNFRSF) molecules are highly expected due to their high potential to enhance survival, proliferation, and effector function of T cells. To date, agonistic antibodies (Abs) against CD27, GITR, OX40, and 4-1BB have been reported to increase the efficacy of anti-PD-1 therapy in animal models and clinical trials of these combinatorial therapies are underway. However, the mechanisms how agonistic Abs against TNFRSF molecules potentiate anti-PD-1 therapy are not well understood. Here we examined the potency of PD-1 to inhibit the antigen-dependent activation of T cells in the presence of co-stimulation through CD27 and GITR by using in vitro and ex vivo co-culture systems of T cells and antigen presenting cells. The cytokine secretion from T cells upon antigen stimulation was strongly augmented by the engagement of CD27 or GITR with their corresponding ligands. Remarkably, PD-1 efficiently inhibited the activation of T cells even in the presence of co-stimulation through CD27 or GITR. Accordingly, cytokine secretion was synergistically augmented when PD-1 blockade was combined with triggering of CD27 or GITR. These results indicate that the triggering of TNFRSF molecules and PD-1 blockade can act on the same individual cells simultaneously to augment the magnitude of T cell activation, providing the rationale for the combinatorial usage of agonistic Abs against TNFRSF molecules and blocking Abs against PD-1 or PD-L1.
掲載誌名
Biochemical and Biophysical Research Communications
ISSN
0006291X
10902104
cat書誌ID
AA00564395
AA11542044
出版者
Elsevier
511
3
開始ページ
491
終了ページ
497
発行日
2019-02-14
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Reina Mizunoの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
© 2019 Published by Elsevier Inc.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3267号
学位記番号
甲医第1416号
学位授与年月日
2019-03-19
学位名
博士(医学)
学位授与機関
徳島大学
部局
先端酵素学研究所