Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression
Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression
复制标题
免疫检查点蛋白VISTA通过控制髓细胞介导的炎症和免疫抑制调节抗肿瘤免疫
DOI：
10.1158/2326-6066.cir-18-0489
复制
发表时间：
2019-09-01
影响因子：
10.1
通讯作者：
Wang, Li
中科院分区：
文献类型：
--
作者：
Xu, Wenwen;Dong, Juan;Wang, Li
免疫检查点蛋白V域免疫球蛋白T细胞激活抑制因子(VistA)控制抗肿瘤免疫，是肿瘤免疫治疗的重要靶点。本研究确定了Vista在调节髓系细胞中的Toll样受体(TLR)信号和控制髓系细胞介导的炎症和免疫抑制中的作用。Vista调节TRAF6的多泛素化和蛋白表达。因此，Vista抑制了TLR介导的MAPK/AP-1和IKK/NF-kappa B信号通路的激活。在细胞水平上，Vista调节髓系来源的抑制细胞和耐受性树突状细胞(DC)亚群的效应功能。阻断Vista增强了他们产生促炎介质的能力，并削弱了他们的T细胞抑制功能。这些髓系细胞依赖的效应导致了刺激的肿瘤微环境，促进了T细胞的渗透和激活。我们得出结论，VistA是一种关键的髓系细胞固有免疫检查点蛋白，VistA阻断后耐受性髓系细胞的重新编程促进了T细胞介导的抗肿瘤免疫的发展。
Immune-checkpoint protein V-domain immunoglobulin suppressor of T-cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. This study identified a role of VISTA in regulating Toll-like receptor (TLR) signaling in myeloid cells and controlling myeloid cell-mediated inflammation and immunosuppression. VISTA modulated the polyubiquitination and protein expression of TRAF6. Consequently, VISTA dampened TLR-mediated activation of MAPK/AP-1 and IKK/NF-kappa B signaling cascades. At cellular levels, VISTA regulated the effector functions of myeloid-derived suppressor cells and tolerogenic dendritic cell (DC) subsets. Blocking VISTA augmented their ability to produce proinflammatory mediators and diminished their T cell-suppressive functions. These myeloid cell-dependent effects resulted in a stimulatory tumor microenvironment that promoted T-cell infiltration and activation. We conclude that VISTA is a critical myeloid cell-intrinsic immune-checkpoint protein and that the reprogramming of tolerogenic myeloid cells following VISTA blockade promotes the development of T cell-mediated antitumor immunity.