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首页> 外文期刊>Molecular cancer therapeutics >Blockade of mTOR Signaling via Rapamycin Combined with Immunotherapy Augments Antiglioma Cytotoxic and Memory T-Cell Functions
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Blockade of mTOR Signaling via Rapamycin Combined with Immunotherapy Augments Antiglioma Cytotoxic and Memory T-Cell Functions

机译：雷帕霉素结合免疫疗法增强mTOR信号传导阻滞神经胶质瘤的细胞毒性和记忆T细胞功能

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The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8(+) T cells. Rats treated with rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV-treated GL26 tumor-bearing mice, associated with an increase in the frequency of tumor-specific and IFN gamma(+) CD8(+) T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8(+) T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8(+) T cells within the tumor and IFN gamma release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM. (C) 2014 AACR.
机译：靶向多形性胶质母细胞瘤（GBM）的免疫治疗方法的成功需要强大的抗神经胶质瘤T细胞细胞毒性和记忆反应。最近的证据表明雷帕霉素调节T细胞分化。在这里，我们测试了雷帕霉素的给药是否可以增强利用Fms样酪氨酸激酶3配体（Ad-Flt3L）和胸苷激酶/更昔洛韦（Ad-TK / GCV）的免疫疗法的功效。使用难治性大鼠RG2胶质瘤模型，我们证明雷帕霉素联合Ad-Flt3L + Ad-TK / GCV免疫疗法的给药可增强抗肿瘤CD8（+）T细胞的细胞毒活性。雷帕霉素+ Ad-Flt3L + Ad-TK / GCV处理的大鼠肿瘤体积显着减少，生存期延长。雷帕霉素的给药还延长了Ad-Flt3L + Ad-TK / GCV治疗的GL26荷瘤小鼠的存活，与肿瘤特异性和IFN gamma（+）CD8（+）T细胞频率增加相关。更重要的是，雷帕霉素的给药，即使间隔很短，也能引起持久有效的中央记忆CD8（+）T细胞应答。增强的记忆反应转化为增加的肿瘤特异性CD8（+）T细胞在肿瘤内和IFNγ释放的频率，为小鼠提供了应对肿瘤再发的长期生存优势。因此，我们的数据指出，雷帕霉素是一种有吸引力的佐剂，可在GBM的I期临床试验中与免疫疗法联合使用。 （C）2014 AACR。

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