Naïve CD8(+) T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment.
Naïve CD8(+) T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment.
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DOI：
10.1038/srep28208
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发表时间：
2016-06-16
影响因子：
4.6
通讯作者：
Yang DH
中科院分区：
文献类型：
--
作者：
Nguyen HH;Kim T;Song SY;Park S;Cho HH;Jung SH;Ahn JS;Kim HJ;Lee JJ;Kim HO;Cho JH;Yang DH
尽管对癌症免疫治疗有潜在的影响，但使用体外扩增的CD8+ T细胞的传统方法结果不理想，主要是由于细胞衰竭导致功能丧失。因此，我们研究了三种不同来源的体外活化CD8+ T细胞的表型和功能差异，即naïve (NTeff)，记忆（MTeff）和肿瘤浸润淋巴细胞（TILeff）来自人和小鼠，以更好地了解强大效应功能背后的机制和克服当前局限性的潜力。与NTeff群体更强的增殖活性和更长的端粒长度一致，naïve来源的细胞比MTeff和TILeff的细胞表现出更少的T细胞衰竭标志物，并且获得了不同的记忆促进转录因子T-bet和Eomes的表达模式，并以快速和可持续的方式诱导。在TGF-β调节下，NTeff细胞Foxp1表达较低，且不易凋亡，表明其具有更好的生存潜力和抗肿瘤诱导的免疫抑制能力。在被肿瘤特异性ctl激活的CD8+ T细胞池中，naïve细胞产生的效应物具有最有效的细胞毒性活性，验证了在合理设计过继免疫治疗中的应用意义。
Despite of the potential implications for cancer immunotherapy, conventional approaches using in vitro expanded CD8+ T cells have suboptimal outcomes, mostly due to loss of functionality from cellular exhaustion. We therefore investigated the phenotypic and functional differences among in vitro activated CD8+ T cells of three different sources, namely naïve (NTeff), memory (MTeff) and tumor-infiltrating lymphocytes (TILeff) from human and mice, to better understand mechanisms behind potent effector functions and potential for overcoming current limitations. In line with the greater proliferation activity and longer telomere lengths of NTeff populations, cells of naïve origin exhibited significantly less amounts of T cell exhaustion markers than those of MTeff and TILeff, and moreover, acquired distinct expression patterns of memory-promoting transcription factors, T-bet and Eomes, induced in a rapid and sustainable manner. NTeff cells appeared to have lower expression of Foxp1 and were refractory to apoptosis upon TGF-β conditioning, implying better survival potential and resistance to tumor-induced immune suppression. Of CD8+ T cell pools activated to tumor-specific CTLs, naïve cell generated effectors possessed the most potent cytotoxic activity, validating implications for use in rational design of adoptive immunotherapy.