Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens
Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens
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DOI：
10.1158/0008-5472.can-10-0247
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发表时间：
2010-10-01
期刊：
影响因子：
11.2
通讯作者：
Davila, Eduardo
中科院分区：
文献类型：
--
作者：
Geng, Degui;Zheng, Liqin;Davila, Eduardo
基于T细胞的免疫疗法治疗癌症患者的功效仍然是一个挑战，部分原因是对亚显性肿瘤抗原（TAg）和表达次优TAg水平的肿瘤的弱活性。最近的报道表明，Toll样受体（TLR）刺激T细胞可以降低激活阈值。在这项研究中，我们研究了TLR 2-MyD 88刺激的CD 8 T细胞的抗肿瘤活性和生存来自黑色素瘤患者和T细胞受体转基因pmel小鼠。TLR 2刺激的pmel CD 8 T细胞，而不是TLR 2（-/-）pmel或MyD 88（-/-）pmel T细胞，响应于显著较低的TAg水平，并导致效应分子的产生和细胞毒性增加。用TLR 2配体和pmel T细胞而不是TLR 2（-/-）pmel或MyD 88（-/-）pmel T细胞处理的野生型或MyD 88（-/-）小鼠显示出已建立的黑素瘤肿瘤的肿瘤消退。在TAG特异性T细胞中过表达TLR 2可以根除肿瘤;产生抗肿瘤反应所需的细胞减少了四倍。TLR 2-MyD 88刺激的T细胞的增强的抗肿瘤活性与增加的效应子功能相关，但可能更重要的是与T细胞的存活改善相关。激活患者来源的T细胞中的TLR-MyD 88信号也降低了几种弱免疫原性TAG的激活阈值，导致细胞因子产生、扩增和细胞毒性增加。这些数据突出了以前未被认识到的激活肿瘤反应性T淋巴细胞中TLR-MyD 88信号的作用。Cancer Res; 70（19）; 7442-54. (C)2010年AACR。
The efficacy of T cell-based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T cells can lower the activation threshold. In this study, we examined the antitumor activity and survival of TLR2-MyD88-stimulated CD8 T cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T cells, but not TLR2(-/-) pmel or MyD88(-/-) pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88(-/-) mice treated with TLR2 ligand and pmel T cells, but not TLR2(-/-) pmel or MyD88(-/-) pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88-stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells. Activating TLR-MyD88 signals in patient-derived T cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion, and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T lymphocytes. Cancer Res; 70(19); 7442-54. (C) 2010 AACR.