Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.
Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.
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DOI：
10.1158/0008-5472.can-13-1550
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发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Coukos G
中科院分区：
文献类型：
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作者：
Duraiswamy J;Freeman GJ;Coukos G
肿瘤微环境介导免疫抑制性程序性死亡-1（PD-1）途径的诱导，针对该途径的靶向干预可以帮助恢复抗肿瘤免疫。为了深入了解这些反应，我们使用上皮性卵巢癌（ID 8）的同基因原位小鼠模型研究了T细胞上表达的PD-1与肿瘤微环境中其他细胞上表达的其配体（PD-1：PD-L1、PD-1：PD-L2和PD-L1：B7.1）之间的相互作用。肿瘤浸润淋巴细胞（TIL）的耗竭与肿瘤细胞和肿瘤源性骨髓细胞（包括巨噬细胞（TAM）、树突状细胞（DC）和骨髓源性抑制细胞（MDSC））表达PD-1配体相关。当与GVAX或FVAX疫苗接种（由表达GM-CSF或FLT 3配体的辐照ID 8细胞组成）和激动性α4-1BB或TLR 9配体的共刺激组合时，抗体介导的PD-1或PD-L1阻断在75%的荷瘤小鼠中引发了ID 8肿瘤的排斥。这种治疗效果与肿瘤抗原特异性效应CD 8 + T细胞的增殖和功能增加、抑制性T调节细胞（TlR）和MDSC的抑制、效应T细胞信号传导分子的上调和T记忆前体细胞的产生相关。总体而言，PD-1/PD-L1阻断通过重新编程抑制和刺激信号增强了肿瘤免疫的幅度，从而产生更强大的癌症控制。
The tumor microenvironment mediates induction of the immunosuppressive programmed death-1 (PD-1) pathway, targeted interventions against which can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1) expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TILs) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including macrophages (TAM), dendritic cells (DC) and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing GM-CSF or FLT3 ligand) and co-stimulation by agonistic α4-1BB or TLR 9 ligand, antibody mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8+ T cells, inhibition of suppressive T regulatory cells (Tregs) and MDSC, upregulation of effector T cell signaling molecules and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.