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GITR 자극을 통한 항암 면역 치료의 작용 기전에 대한 연구 : Studies on the mechanism of GITR-modulating antitumor immunotherapy
DC Field | Value | Language |
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dc.contributor.advisor | 강창율 | - |
dc.contributor.author | 김일규 | - |
dc.date.accessioned | 2017-07-13T16:36:10Z | - |
dc.date.available | 2017-07-13T16:36:10Z | - |
dc.date.issued | 2015-08 | - |
dc.identifier.other | 000000056825 | - |
dc.identifier.uri | https://hdl.handle.net/10371/120100 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 약학과(의약생명과학전공), 2015. 8. 강창율. | - |
dc.description.abstract | Recently, immunotherapies using blocking monoclonal antibodies (mAbs) to immune check points, such as CTLA-4 and PD-1, have shown meaningful results in cancer clinics. Glucocorticoid-induced TNF receptor family-related protein (GITR) is a costimulatory molecule that has emerged as a promising target for the treatment of cancer. In various mouse models of tumors, GITR stimulation has displayed strong antitumor activity and human GITR-targeting mAbs are currently under two phase I clinical trials. Despite the well-known antitumor effect of agonistic GITR mAbs, the underlying mechanism of action remains unclear. Here, I demonstrate a crucial role for IL-9 in antitumor immunity generated by the GITR agonistic antibody, DTA-1. Il4ra-/- mice were resistant to tumor growth inhibition by DTA-1, which was associated with reduced expression of IL-9 by CD4+ T cells. More importantly, an antibody against IL-9 significantly incapacitated tumor rejection by DTA-1. Mechanistically, GITR costimulation intrinsically enhanced IL-9 expression by CD4+ T cells in a TRAF6-NF-κB dependent manner, while it inhibited the generation of induced Treg cells in vitro and down-regulated Foxp3 expression in induced Treg cells in vivo.
Furthermore, administration of anti-GITR augmented tumor-specific cytotoxic T cell responses in an IL-9-dependent manner, which was accompanied by increased maturation and cross-presentation capacity of infiltrating dendritic cells (DCs). Therefore, our findings demonstrate that GITR costimulation mediates antitumor immunity by promoting TH9 cell differentiation and thus provide a mechanism of action for GITR-mediated anti-cancer immunotherapeutic approaches. | - |
dc.description.tableofcontents | Abstract…………………………………………………………… i
Table of Contents……………………………………………… iv List of Figures………………………………………………… vi Abbreviations………………………………………………… viii Introduction……………………………………………………… 1 Materials and Methods……………………………………… 8 Results………………………………………………………… 17 - IL-4R signaling is required for GITR agonist-induced tumor regression ……… 17 - IL-9 mediates antitumor activity induced by anti-GITR ……………………… 20 - Anti-GITR drives TH9 differentiation in a T cell-intrinsic manner …………… 25 - Anti-GITR inhibits the generation and maintenance of induced Treg cells …… 30 - TRAF6-NF-κB pathway is required for GITR-mediated TH9 differentiation … 41 - IL-9 triggered by anti-GITR potentiates tumor-specific CTL responses ……… 47 - GITR-induced IL-9 activates tumor-infiltrating DCs in vivo …………………… 51 Discussion……………………………………………………… 56 References……………………………………………………… 64 국문 초록………………………………………………………… 72 | - |
dc.format | application/pdf | - |
dc.format.extent | 2997926 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | GITR | - |
dc.subject | IL-9 | - |
dc.subject | Th9 | - |
dc.subject | antitumor immunotherapy | - |
dc.subject.ddc | 615 | - |
dc.title | GITR 자극을 통한 항암 면역 치료의 작용 기전에 대한 연구 | - |
dc.title.alternative | Studies on the mechanism of GITR-modulating antitumor immunotherapy | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Il-Kyu Kim | - |
dc.description.degree | Doctor | - |
dc.citation.pages | x, 73 | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2015-08 | - |
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