Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication
Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication
复制标题
DOI：
10.1158/0008-5472.can-15-0454
复制
发表时间：
2015-08-15
期刊：
影响因子：
11.2
通讯作者：
Leclerc, Claude
中科院分区：
文献类型：
--
作者：
Chaoul, Nada;Fayolle, Catherine;Leclerc, Claude
代谢感受器mTOR广泛调节癌细胞的生长和分裂，导致雷帕霉素及其类似物作为候选抗癌药物的研究受到极大关注。然而，mTOR抑制剂未能产生有用的临床疗效，可能是因为mTOR在参与免疫监控的T细胞中也是关键的。事实上，最近使用雷帕霉素的研究已经证明了mTOR在分化和诱导与抗肿瘤特性相关的T细胞反应中的CD8(+)记忆中的重要作用。在这项研究中，我们证明了在肿瘤疫苗治疗的背景下，雷帕霉素损害了T细胞介导的抗肿瘤免疫反应。具体地说，我们分析了雷帕霉素如何影响人乳头瘤病毒E7多肽疫苗(CyaA-E7)的抗肿瘤效果，该疫苗能够根除TC-1小鼠宫颈癌模型中的肿瘤。在接种了CyaA-E7的动物中，雷帕霉素完全取消了CD8(+)T细胞在TC-1肿瘤中的募集，同时疫苗还能够减少T调节细胞和髓系来源的抑制细胞的渗透。此外，雷帕霉素完全取消了疫苗诱导的细胞毒性T细胞反应和治疗活性。综上所述，我们的结果表明，mTOR抑制在取消T细胞介导的抗肿瘤免疫反应方面具有强大的作用，而T细胞介导的抗肿瘤免疫反应是癌症疫苗治疗效果所必需的。(C)2015年AACR。
The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8(+) memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of ahuman papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8(+) T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell-mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines. (C) 2015 AACR.