ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40-Mediated Tumor Rejection
ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40-Mediated Tumor Rejection
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DOI：
10.1158/0008-5472.can-15-3412
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Feldman, Reid M. R.
中科院分区：
文献类型：
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作者：
Metzger, Todd C.;Long, Hua;Feldman, Reid M. R.
ICOS是一种T细胞共调节受体，在抗原介导的活化过程中向T细胞提供共刺激信号。抗肿瘤免疫可以通过ICO靶向治疗来改善，但其作用机制尚不清楚。在这里，我们定义的作用ICOS信号在抗肿瘤免疫使用的阻断，非消耗性抗体ICOS配体（ICOS-L）。ICOS信号传导为CD 4（+）Foxp 3（-）T细胞在抗OX 40驱动的肿瘤免疫应答期间的效应子功能提供了关键支持。ICOS-L阻断本身减少了肿瘤内调节性T细胞（T-reg）的积累，但不足以显著抑制肿瘤生长。此外，它不阻碍抗4- 1BB驱动的CD 8（+）T细胞介导的抗肿瘤反应。我们发现，抗OX 40的功效，这是基于T-reg耗竭，并在很大程度上对CD 4（+）效应T细胞（T-eff）的反应，是受损的ICOS-L封锁。相比之下，当沿着抗OX 40疗法施用时，通过肿瘤细胞的直接ICOS-L表达提供额外的ICOS信号传导增强了肿瘤排斥和存活。总之，我们的结果表明，抗肿瘤反应期间的ICOS信号传导作用于T-eff和T-reg细胞，这两种细胞在促进免疫激活方面具有相反的作用。因此，靶向ICOS通路的有效疗法应该寻求通过结合ICOS激动和T-reg耗竭来促进效应CD 4（+）T细胞中特异性的ICOS信号传导。(C)2016年AACR。
ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumorimmunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4(+) Foxp3(-) T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (T-reg), but it was insufficient to substantially inhibit tumorgrowth. Furthermore, it did notimpede antitumor responses mediated by anti-4-1BB-drivenCD8(+) T cells. We found that anti-OX40 efficacy, which is based on T-reg depletion and to a large degree on CD4(+) effector T cell (T-eff) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both T-eff and T-reg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4(+) T cells by combining ICOS agonism and T-reg depletion. (C) 2016 AACR.