Chen Aoshuang, Liu Shanrong, Park David, Kang Youmin, Zheng Guoxing
Department of Biomedical Sciences, College of Medicine at Rockford, University of Illinois, 1601 Parkview Avenue, Rockford, IL 61107, USA.
Cancer Res. 2007 Feb 1;67(3):1291-8. doi: 10.1158/0008-5472.CAN-06-2622.
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 intratumoral 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.
一种改善过继性治疗的策略是通过清除对抗肿瘤反应具有抑制作用的CD4(+)CD25(+)调节性T细胞（Treg）来预处理宿主免疫环境。鉴于Treg在肿瘤内增加或选择性积聚，并且对FasL介导的凋亡敏感，我们在此测试使用FasL诱导肿瘤内Treg凋亡可能改善过继性T细胞治疗的假设。我们表明，通过蛋白质转导瘤内应用FasL可通过诱导这些细胞凋亡来减少肿瘤内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细胞转移对已建立肿瘤的治疗效果，这是由持续的全身抗肿瘤免疫介导的。瘤内FasL蛋白质转导还导致肿瘤的中性粒细胞浸润。然而，我们表明瘤内中性粒细胞免疫清除并不消除FasL对过继性转移的作用。相反，从肿瘤引流淋巴结分离的Treg共转导可完全消除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为优化过继性治疗提供了一种有用的方法。
