Depleting intratumoral CD4+CD25+ regulatory T cells via FasL protein transfer enhances the therapeutic efficacy of adoptive T cell transfer
Depleting intratumoral CD4+CD25+ regulatory T cells via FasL protein transfer enhances the therapeutic efficacy of adoptive T cell transfer
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DOI：
10.1158/0008-5472.can-06-2622
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Zheng, Guoxing
中科院分区：
文献类型：
--
作者：
Chen, Aoshuang;Liu, Shanrong;Zheng, Guoxing
一种改进过继性疗法的策略是通过清除对肿瘤反应起抑制作用的CD4(+)CD25(+)调节性T细胞（Treg）来预处理宿主免疫环境。鉴于Treg在肿瘤内增多或选择性聚集，并且对FasL介导的细胞凋亡敏感，我们在此验证一个假设，即使用FasL诱导肿瘤内Treg凋亡可能会改进过继性T细胞疗法。我们发现通过蛋白质转移在肿瘤内应用FasL可通过诱导这些细胞凋亡来减少肿瘤内的Treg。重要的是，我们表明在输注肿瘤反应性CD8(+)T细胞之前使用FasL可增强过继性T细胞转移对已形成肿瘤的治疗效果，这是由持久的全身性抗肿瘤免疫所介导的。肿瘤内FasL蛋白质转移还导致肿瘤中性粒细胞浸润。然而，我们发现肿瘤内中性粒细胞的免疫清除并不会消除FasL对过继性转移的影响。相反，从肿瘤引流淋巴结分离出的Treg共转移会完全消除FasL的作用。因此，我们的研究首次表明，使用FasL预先清除肿瘤内Treg为优化过继性疗法提供了一种有用的手段。
One strategy for improving adoptive therapy is preconditioning the host immune environment by depleting CD4(+)CD25(+) regulatory T cells (Treg) suppressive to antitumor responses. Given that Treg increase, or selectively accumulate, within tumors and are sensitive to FasL-mediated apoptosis, we test here the hypothesis that inducing apoptosis of intratumoral Treg using FasL may improve adoptive T cell therapy. We show that FasL applied intratumorally via protein transfer decreases intratumoral Treg via inducing apoptosis in these cells. Significantly, we show that the use of FasL prior to the infusion of tumor-reactive CD8(+) T cells enhances the therapeutic efficacy of adoptive T cell transfer against established tumors, which is mediated by persistent, systemic antitumor immunity. Intratumoral FasL protein transfer also results in neutrophil infiltration of tumor. However, we show that intra-tumoral immunodepletion of neutrophils does not abolish the effect of FasL on adoptive transfer. Rather, the effect of FasL is completely abolished by cotransfer of Treg, isolated from the tumor-draining lymph nodes. Hence, our study shows for the first time that using FasL to predeplete intratumoral Treg provides a useful means for optimizing adoptive therapy.