PD-1 efficiently inhibits T cell activation even in the presence of co-stimulation through CD27 and GITR
PD-1 efficiently inhibits T cell activation even in the presence of co-stimulation through CD27 and GITR
复制标题
即使在通过 CD27 和 GITR 共刺激的情况下，PD-1 也能有效抑制 T 细胞活化
DOI：
10.1016/j.bbrc.2019.02.004
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发表时间：
2019
影响因子：
3.1
通讯作者：
Okazaki Taku
中科院分区：
文献类型：
--
作者：
Mizuno Reina;Maruhashi Takumi;Sugiura Daisuke;Shimizu Kenji;Watada Mizuki;Okazaki Il-mi;Okazaki Taku
靶向程序性细胞死亡1（PD-1）和细胞毒性T淋巴细胞抗原4的癌症免疫疗法彻底改变了癌症治疗，并引发了各种试验以开发具有更高疗效的新癌症免疫疗法。针对肿瘤坏死因子受体超家族（TNFRSF）分子的激动性Ab由于其增强T细胞的存活、增殖和效应子功能的高潜力而备受期待。迄今为止，已经报道了针对CD 27、GITR、0X 40和4-1BB的激动性抗体（Ab）在动物模型中增加抗PD-1疗法的功效，并且这些组合疗法的临床试验正在进行中。然而，针对TNFRSF分子的激动性Ab如何增强抗PD-1治疗的机制尚未得到很好的理解。在此，我们通过使用T细胞和抗原呈递细胞的体外和离体共培养系统，检查了PD-1在通过CD 27和GITR的共刺激存在下抑制T细胞的抗原依赖性活化的效力。抗原刺激后T细胞的细胞因子分泌通过CD 27或GITR与其相应配体的接合而强烈增强。值得注意的是，即使在存在通过CD 27或GITR的共刺激的情况下，PD-1也有效地抑制了T细胞的活化。因此，当PD-1阻断与CD 27或GITR的触发组合时，细胞因子分泌协同增强。这些结果表明，TNFRSF分子的触发和PD-1阻断可以同时作用于相同的单个细胞以增加T细胞活化的幅度，这为针对TNFRSF分子的激动性Ab和针对PD-1或PD-L1的阻断性Ab的组合使用提供了理论基础。
Cancer immunotherapies targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 revolutionized cancer treatment and instigated various trials to develop new cancer immunotherapies with higher therapeutic efficacy. Agonistic Abs against tumor necrosis factor receptor super family (TNFRSF) molecules are highly expected due to their high potential to enhance survival, proliferation, and effector function of T cells. To date, agonistic antibodies (Abs) against CD27, GITR, OX40, and 4-1BB have been reported to increase the efficacy of anti-PD-1 therapy in animal models and clinical trials of these combinatorial therapies are underway. However, the mechanisms how agonistic Abs against TNFRSF molecules potentiate anti-PD-1 therapy are not well understood. Here we examined the potency of PD-1 to inhibit the antigen-dependent activation of T cells in the presence of co-stimulation through CD27 and GITR by using in vitro and ex vivo co-culture systems of T cells and antigen presenting cells. The cytokine secretion from T cells upon antigen stimulation was strongly augmented by the engagement of CD27 or GITR with their corresponding ligands. Remarkably, PD-1 efficiently inhibited the activation of T cells even in the presence of co-stimulation through CD27 or GITR. Accordingly, cytokine secretion was synergistically augmented when PD-1 blockade was combined with triggering of CD27 or GITR. These results indicate that the triggering of TNFRSF molecules and PD-1 blockade can act on the same individual cells simultaneously to augment the magnitude of T cell activation, providing the rationale for the combinatorial usage of agonistic Abs against TNFRSF molecules and blocking Abs against PD-1 or PD-L1.