Enhanced Tumor Eradication by Combining CTLA-4 or PD-1 Blockade With CpG Therapy
Enhanced Tumor Eradication by Combining CTLA-4 or PD-1 Blockade With CpG Therapy
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DOI：
10.1097/cji.0b013e3181c01fcb
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发表时间：
2010-04-01
影响因子：
3.9
通讯作者：
Totterman, Thomas H.
中科院分区：
文献类型：
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作者：
Mangsbo, Sara M.;Sandin, Linda C.;Totterman, Thomas H.
肿瘤免疫治疗的目的是打破效应t细胞的能量，阻断抑制细胞类型和配体，使效应细胞发挥肿瘤根除作用。先前的报告表明，细胞毒性T淋巴细胞抗原-4 （CTLA-4）阻断抗体促进T细胞活化并使T效应细胞对T调节细胞（Tregs）产生抗性，而程序性死亡受体-1 (PD-1)/PD-L1阻断导致外周耐受性丧失。本研究探索CTLA-4和PD-1单独或联合抗体阻断或与toll样受体激动剂CpG或卡介苗- guerin联合治疗小鼠实验性膀胱癌。在治疗研究中，抗ctla -4 （aCTLA-4）会对肿瘤产生排斥反应，而抗pd -1 （aPD-1）会抑制肿瘤生长。与aCTLA-4单用相比，联合用药无加性效应。然而，在aCTLA-4 + aPD-1组中，循环CD107a表达CD8(+) T细胞水平升高。此外，抗核抗体水平与肿瘤大小呈负相关。接下来，我们将CpG或Calmette-Guerin杆菌与aCTLA-4、aPD-1或aPD-L1联合使用，发现CpG与aCTLA-4或aPD-1联合使用可提高小鼠的存活率，且aPD-1加CpG优于单独使用任何一种药物。CpG + aCTLA-4或aPD-1增加循环肿瘤特异性CD107a表达CD8(+) T细胞的数量以及活化(CD25(+) FoxP3(-)) CD4（+）脾细胞的数量。此外，我们研究了治疗动物肿瘤区域的Tregs数量，发现aCTLA-4或aPD-1加CpG治疗后Tregs水平下降。因此，CpG联合CTLA-4或PD-1阻断改善了长期生存，导致肿瘤反应性T细胞水平增加，肿瘤部位Tregs数量减少。
Tumor immunotherapy aims to break effector T-cell anergy and to block suppressive cell types and ligands allowing effector cells to exert tumor eradication. Previous reports demonstrate that cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibodies promote T-cell activation and render T effector cells resistant to T regulatory cells (Tregs) whereas programmed death receptor-1 (PD-1)/PD-L1 blockade results in loss of peripheral tolerance. Herein, we explored single or combined antibody blockade of CTLA-4 and PD-1 alone or combined with the toll-like receptor agonists CpG or bacillus Calmette-Guerin for treatment of murine experimental bladder cancer. In therapeutic studies, tumors were rejected by anti-CTLA-4 (aCTLA-4) while anti-PD-1 (aPD-1) suppressed tumor growth. The combination had no additive effect compared with aCTLA-4 alone. However, elevated levels of circulating CD107a expressing CD8(+) T cells were found in the aCTLA-4 plus aPD-1 group. In addition, levels of antinuclear antibodies correlated inversely with tumor size. Next, we combined CpG or bacillus Calmette-Guerin with aCTLA-4, aPD-1, or aPD-L1 and found that CpG in combination with aCTLA-4 or aPD-1 increased the survival of mice, with aPD-1 plus CpG being superior to either agent alone. CpG plus aCTLA-4 or aPD-1 increased the numbers of circulating tumor-specific CD107a expressing CD8(+) T cells as well as activated (CD25(+) FoxP3(-)) CD4(+) splenocytes. Further, we investigated the numbers of Tregs in the tumor area of treated animals and detected decreased levels after aCTLA-4 or aPD-1 plus CpG therapy. Thus, the combination of CpG with CTLA-4 or PD-1 blockade improved long-term survival and led to increased levels of tumor-reactive T cells and reduced numbers of Tregs at the tumor site.