CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma.
CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma.
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DOI：
10.1007/s00262-014-1598-8
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发表时间：
2014-11
影响因子：
5.8
通讯作者：
Griffith, Thomas S.
中科院分区：
文献类型：
--
作者：
James, Britnie R.;Anderson, Kristin G.;Brincks, Erik L.;Kucaba, Tamara A.;Norian, Lyse A.;Masopust, David;Griffith, Thomas S.
肿瘤进展通过调节许多生理参数发生，包括免疫抑制机制的发展以防止免疫检测和应答。在这些免疫逃避机制中，髓源性抑制细胞（MDSC）的动员是抑制抗肿瘤T细胞免疫的主要贡献者。肾细胞癌（RCC）患者显示MDSC增加，临床上正在探索降低MDSC患病率和/或抑制其功能的方法。在本研究中，我们研究了MDSC和TRAIL编码的重组腺病毒（Ad 5-TRAIL）与含CpG的寡脱氧核苷酸（Ad 5-TRAIL/CpG）组合在RCC原位小鼠模型中的治疗潜力之间的关系。这种免疫疗法有效地清除肾（Renca）肿瘤并提高生存率，尽管在治疗时脾脏和原发性荷瘤肾脏中存在高频率的MDSC。随后的分析显示，免疫治疗的CpG组分负责降低Renca荷瘤小鼠中MDSC的频率;此外，用CpG治疗调节了免疫治疗后保留的MDSC的表型和功能，并与增加的T细胞应答相关。有趣的是，MDSC频率和功能的CpG依赖性改变并没有发生在患有饮食诱导的肥胖症的荷瘤小鼠中。总的来说，这些数据表明，除了其佐剂特性外，CpG还通过改变MDSC的数量和功能来增强抗肿瘤反应。
Tumor progression occurs through the modulation of a number of physiological parameters, including the development of immunosuppressive mechanisms to prevent immune detection and response. Among these immune evasion mechanisms, the mobilization of myeloid-derived suppressor cells (MDSC) is a major contributor to the suppression of antitumor T-cell immunity. Patients with renal cell carcinoma (RCC) show increased MDSC, and methods are being explored clinically to reduce the prevalence of MDSC and/or inhibit their function. In the present study, we investigated the relationship between MDSC and the therapeutic potential of a TRAIL-encoding recombinant adenovirus (Ad5-TRAIL) in combination with CpG-containing oligodeoxynucleotides (Ad5-TRAIL/CpG) in an orthotopic mouse model of RCC. This immunotherapy effectively clears renal (Renca) tumors and enhances survival, despite the presence of a high frequency of MDSC in the spleens and primary tumor-bearing kidneys at the time of treatment. Subsequent analyses revealed that the CpG component of the immunotherapy was responsible for decreasing the frequency of MDSC in Renca-bearing mice; further, treatment with CpG modulated the phenotype and function of MDSC that remained after immunotherapy and correlated with an increased T-cell response. Interestingly, the CpG-dependent alterations in MDSC frequency and function did not occur in tumor-bearing mice complicated with diet-induced obesity. Collectively, these data suggest that in addition to its adjuvant properties, CpG also enhances antitumor responses by altering the number and function of MDSC.
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影响因子：
2.2
作者：
HRUSHESKY, WJ;MURPHY, GP
通讯作者：
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