PDF(Pubmed)
Abstract：
Immune checkpoint inhibitors have changed the treatment landscape for various malignancies; however, their benefit is limited to a subset of patients. The immune machinery includes both mediators of suppression/immune evasion, such as PD-1, PD-L1, CTLA-4, and LAG-3, all of which can be inhibited by specific antibodies, and immune-stimulatory molecules, such as T-cell co-stimulatory receptors that belong to the tumor necrosis factor receptor superfamily (TNFRSF), including OX40 receptor (CD134; TNFRSF4), 4-1BB (CD137; TNFRSF9), and glucocorticoid-induced TNFR-related (GITR) protein (CD357; TNFRSF18). In particular, OX40 and its binding ligand OX40L (CD134L; TNFSF4; CD252) are critical for immunoregulation. When OX40 on activated T cells binds OX40L on antigen-presenting cells, T-cell activation and immune stimulation are initiated via enhanced T-cell survival, proliferation and cytotoxicity, memory T-cell formation, and abrogation of regulatory T cell (Treg) immunosuppressive functions. OX40 agonists are in clinical trials both as monotherapy and in combination with other immunotherapy agents, in particular specific checkpoint inhibitors, for cancer treatment. To date, however, only a minority of patients respond. Transcriptomic profiling reveals that OX40 and OX40L expression vary between and within tumor types, and that only ~ 17% of cancer patients have high OX40 and low OX40L, one of the expression patterns that might be theoretically amenable to OX40 agonist enhancement. Taken together, the data suggest that the OX40/OX40L machinery is a critical part of the immune stimulatory system and that understanding endogenous expression patterns of these molecules and co-existing checkpoints merits further investigation in the context of a precision immunotherapy strategy for cancer therapy.
摘要：
免疫检查点抑制剂改变了各种恶性肿瘤的治疗前景；然而，他们的获益仅限于一部分患者.免疫机制包括抑制/免疫逃避的介质，如PD-1，PD-L1，CTLA-4和LAG-3，所有这些都可以被特异性抗体抑制，和免疫刺激分子，例如属于肿瘤坏死因子受体超家族（TNFRSF）的T细胞共刺激受体，包括OX40受体（CD134;TNFRSF4），4-1BB(CD137;TNFRSF9),和糖皮质激素诱导的TNFR相关（GITR）蛋白（CD357;TNFRSF18）。特别是,OX40及其结合配体OX40L(CD134L;TNFSF4;CD252)对于免疫调节至关重要。当活化T细胞上的OX40结合抗原呈递细胞上的OX40L时，T细胞活化和免疫刺激是通过增强T细胞存活启动的。增殖和细胞毒性，记忆T细胞形成，和取消调节性T细胞(Treg)免疫抑制功能。OX40激动剂作为单一疗法和与其他免疫治疗剂的组合都在临床试验中。特别是特定的检查点抑制剂，癌症治疗。迄今为止,然而,只有少数患者有反应。转录组学分析显示，OX40和OX40L表达在肿瘤类型之间和内部不同，只有约17%的癌症患者有高OX40和低OX40L，理论上可能适合OX40激动剂增强的表达模式之一。一起来看,数据表明,OX40/OX40L机制是免疫刺激系统的关键部分,了解这些分子的内源性表达模式和共存检查点,值得在癌症治疗的精准免疫治疗策略中进一步研究.
