GITR 자극을 통한 항암 면역 치료의 작용 기전에 대한 연구
Studies on the mechanism of GITR-modulating antitumor immunotherapy
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과(의약생명과학전공), 2015. 8. 강창율.
- 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.