Programmed Death Ligand 1 (PD-L1)-targeted TRAIL combines PD-L1-mediated checkpoint inhibition with TRAIL-mediated apoptosis induction.
Programmed Death Ligand 1 (PD-L1)-targeted TRAIL combines PD-L1-mediated checkpoint inhibition with TRAIL-mediated apoptosis induction.
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DOI：
10.1080/2162402x.2016.1202390
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发表时间：
2016-08
期刊：
影响因子：
7.2
通讯作者：
Bremer E
中科院分区：
文献类型：
--
作者：
Hendriks D;He Y;Koopmans I;Wiersma VR;van Ginkel RJ;Samplonius DF;Helfrich W;Bremer E
阻断PD-L1/PD-1免疫检查点的抗体可恢复功能受损的抗肿瘤T细胞的活性。这些抗体在各种晚期癌症，特别是黑色素瘤中显示出前所未有的临床益处。然而，只有一部分癌症患者对目前的PD-L1/PD-1阻断策略有反应，这凸显了进一步推进基于PD-L1/PD-1的免疫治疗的必要性。在这里，我们报告了一种新的方法，旨在将联合收割机PD-L1检查点抑制与肿瘤坏死因子相关凋亡诱导配体（TRAIL）的肿瘤选择性诱导凋亡相结合。简而言之，构建了一种新的双功能融合蛋白，称为抗PD-L1：TRAIL，其包含与促凋亡杀肿瘤蛋白TRAIL的细胞外结构域遗传融合的PD-L1阻断抗体片段。用抗PD-L1：TRAIL处理表达PD-L1的癌细胞诱导PD-L1指导的TRAIL介导的癌细胞死亡。用抗PD-L1：TRAIL处理T细胞增强了T细胞活化，如通过在混合T细胞/癌细胞培养实验中增加的增殖、IFNγ的分泌和增强的癌细胞系和原代患者来源的癌细胞的杀伤所证明的。值得注意的是，IFNγ水平升高进一步上调癌细胞上的PD-L1，同时使癌细胞对抗PD-L1：TRAIL介导的凋亡敏感。此外，抗PD-L1：TRAIL将免疫抑制性PD-L1表达骨髓细胞转化为促凋亡效应细胞，从而引发TRAIL介导的癌细胞死亡。总之，使用抗PD-L1：TRAIL将PD-L1检查点抑制与TRAIL介导的细胞凋亡诱导相结合，产生了有希望的多重和相互增强的抗癌活性，可用于增强治疗性PD-L1/PD-1检查点抑制的疗效。
Antibodies that block PD-L1/PD-1 immune checkpoints restore the activity of functionally-impaired antitumor T cells. These antibodies show unprecedented clinical benefit in various advanced cancers, particularly in melanoma. However, only a subset of cancer patients responds to current PD-L1/PD-1-blocking strategies, highlighting the need for further advancements in PD-L1/PD-1-based immunotherapy. Here, we report on a novel approach designed to combine PD-L1 checkpoint inhibition with the tumor-selective induction of apoptosis by TNF-related Apoptosis Inducing Ligand (TRAIL). In brief, a new bi-functional fusion protein, designated anti-PD-L1:TRAIL, was constructed comprising a PD-L1-blocking antibody fragment genetically fused to the extracellular domain of the pro-apoptotic tumoricidal protein TRAIL. Treatment of PD-L1-expressing cancer cells with anti-PD-L1:TRAIL induced PD-L1-directed TRAIL-mediated cancer cell death. Treatment of T cells with anti-PD-L1:TRAIL augmented T cell activation, as evidenced by increased proliferation, secretion of IFNγ and enhanced killing of cancer cell lines and primary patient-derived cancer cells in mixed T cell/cancer cell culture experiments. Of note, elevated levels of IFNγ further upregulated PD-L1 on cancer cells and simultaneously sensitized cancer cells to TRAIL-mediated apoptosis by anti-PD-L1:TRAIL. Additionally, anti-PD-L1:TRAIL converted immunosuppressive PD-L1-expressing myeloid cells into pro-apoptotic effector cells that triggered TRAIL-mediated cancer cell death. In conclusion, combining PD-L1 checkpoint inhibition with TRAIL-mediated induction of apoptosis using anti-PD-L1:TRAIL yields promising multi-fold and mutually reinforcing anticancer activity that may be exploited to enhance the efficacy of therapeutic PD-L1/PD-1 checkpoint inhibition.