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首页> 外文期刊>Vaccine >Lymphocyte-polarized dendritic cells are highly effective in inducing tumor-specific CTLs
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Lymphocyte-polarized dendritic cells are highly effective in inducing tumor-specific CTLs

机译：淋巴细胞极化的树突状细胞在诱导肿瘤特异性CTLs中非常有效

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High activity of dendritic cells (DCs) in inducing cytotoxic T cells (CTLs) led to their application as therapeutic cancer vaccines. The ability of DCs to produce IL-12p70 is one of the key requirements for effective CTL induction and a predictive marker of their therapeutic efficacy in vivo. We have previously reported that defined cocktails of cytokines, involving TNFα and IFNγ, induce mature type-1 polarized DCs (DC1s) which produce strongly elevated levels of IL-12 and CXCL10/IP10 upon CD40 ligation compared to “standard” PGE2-matured DCs (sDCs; matured with IL-1β, IL-6, TNFα, and PGE2) and show higher CTL-inducing activity. Guided by our observations that DC1s can be induced by TNFα- and IFNγ-producing CD8+ T cells, we have tested the feasibility of using lymphocytes to generate DC1s in a clinically-compatible process, to limit the need for clinical-grade recombinant cytokines and the associated costs. CD3/CD28 activation of bulk lymphocytes expanded them and primed them for effective production of IFNγ and TNFα following restimulation. Restimulated lymphocytes, or their culture supernatants, enhanced the maturation status of immature (i)DCs, elevating their expression of CD80, CD83 and CCR7, and the ability to produce IL-12p70 and CXCL10 upon subsequent CD40 ligation. The “lymphocyte-matured” DC1s showed elevated migration in response to the lymph-node-directing chemokine, CCL21, when compared to iDCs. When loaded with antigenic peptides, supernatant-matured DCs induced much high levels of CTLs recognizing tumor-associated antigenic epitope, than PGE2-matured DCs from the same donors. These results demonstrate the feasibility of generation of polarized DC1s using autologous lymphocytes.
机译：树突状细胞（DC）诱导细胞毒性T细胞（CTL）的高活性导致其作为治疗性癌症疫苗的应用。 DC产生IL-12p70的能力是有效诱导CTL的关键要求之一，并且是其体内治疗功效的预测标记。我们之前曾报道过，与TNF-α和IFNγ结合的特定细胞因子混合物诱导成熟的1型极化DC（DC1），与“标准” PGE2成熟的DC相比，CD40连接后产生的IL-12和CXCL10 / IP10的水平大大升高。 （sDC;已与IL-1β，IL-6，TNFα和PGE2一起成熟），并显示出更高的CTL诱导活性。根据我们的观察结果，即DC1s可以被产生TNFα和IFNγ的CD8 + T细胞诱导，我们测试了在临床上兼容的过程中使用淋巴细胞生成DC1的可行性，以限制对临床级重组细胞因子和细胞因子的需求。相关费用。再刺激后，大量淋巴细胞的CD3 / CD28活化使它们扩增并引发它们，以有效产生IFNγ和TNFα。重新刺激的淋巴细胞或其培养物上清液可增强未成熟（i）DC的成熟状态，从而提高其CD80，CD83和CCR7的表达以及随后的CD40连接后产生IL-12p70和CXCL10的能力。与iDCs相比，“淋巴细胞成熟”的DC1s对淋巴结定向趋化因子CCL21的迁移增加。当装载抗原肽时，与来自相同供体的PGE2成熟DC相比，成熟上清成熟的DC诱导识别肿瘤相关抗原表位的CTL水平高得多。这些结果证明使用自体淋巴细胞产生极化DC1的可行性。

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