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ID 113351
Title Alternative
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
Author
Mizuno, Reina Tokushima University
Shimizu, Kenji Tokushima University
Watada, Mizuki Tokushima University
Keywords
PD-1
CD27
GITR
T cell activation
Co-receptor
TNF receptor super family
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Biochemical and Biophysical Research Communications
ISSN
0006291X
10902104
NCID
AA00564395
AA11542044
Publisher
Elsevier
Volume
511
Issue
3
Start Page
491
End Page
497
Published Date
2019-02-14
Remark
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。
Rights
© 2019 Published by Elsevier Inc.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3267号
Diploma Number
甲医第1416号
Granted Date
2019-03-19
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Institute of Advanced Medical Sciences