A soluble form of CD80 enhances antitumor immunity by neutralizing programmed death ligand-1 and simultaneously providing costimulation.
A soluble form of CD80 enhances antitumor immunity by neutralizing programmed death ligand-1 and simultaneously providing costimulation.
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DOI：
10.1158/2326-6066.cir-13-0204
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发表时间：
2014-07
影响因子：
10.1
通讯作者：
Ostrand-Rosenberg S
中科院分区：
文献类型：
--
作者：
Haile ST;Horn LA;Ostrand-Rosenberg S
肿瘤细胞利用各种免疫抑制方法来克服抗肿瘤免疫。其中一种方法是程序性死亡配体-1 (PD-L1或B7-H1)，它将其受体程序性死亡-1 （PD-1）结合在T细胞上，触发活化T细胞的凋亡性死亡。共刺激分子CD80在PD-L1+肿瘤细胞上的过度表达，或CD80的可溶性形式（CD80- fc）的包被维持PD-1+激活的T细胞的激活。利用CD28缺陷小鼠的T细胞和抗体阻断人类T细胞上的CD28，我们现在报告了一种可溶性形式的CD80通过同时中和PD-1/ pd - l1介导的免疫抑制和提供CD80-CD28共刺激来介导这种作用。总之，PD-L1是一种有效的免疫抑制介质，在许多癌症患者中抑制抗肿瘤免疫。在这项研究中，我们发现共刺激分子CD80的可溶性形式比PD-1或PD-L1抗体更有效地增加PD-1+激活的T细胞产生IFNγ。因此，可溶性CD80可能比这些检查点抗体更有效地促进抗肿瘤免疫的发展和维持，因为它具有防止pd - l1介导的免疫抑制和同时传递t细胞激活的第二信号的双重功能。
Tumor cells employ various methods of immune suppression to overcome antitumor immunity. One such method is that of programmed death ligand-1 (PD-L1 or B7-H1), which upon binding its receptor programmed death-1 (PD-1) on T cells triggers apoptotic death of the activated T cells. Over-expression of the costimulatory molecule CD80 on PD-L1+ tumor cells, or inclusion of a soluble form of CD80 (CD80-Fc) maintains the activation of PD-1+ activated T cells. Using T cells from CD28-deficient mice and antibodies to block CD28 on human T cells, we now report that a soluble form of CD80 mediates this effect by simultaneously neutralizing the PD-1/PD-L1-mediated immune suppression and by providing CD80-CD28 costimulation. In summary, PD-L1 is a potent mediator of immune suppression that inhibits antitumor immunity in many cancer patients. In this study, we show that a soluble form of the costimulatory molecule CD80 increases the production of IFNγ by PD-1+ activated T cell more effectively than antibodies to PD-1 or PD-L1. Therefore, soluble CD80 may be a more effective therapeutic than these checkpoint antibodies for facilitating the development and maintenance of antitumor immunity because it has the dual functions of preventing PD-L1-mediated immune suppression and simultaneously delivering the second signal for T-cell activation.