Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

译文

:关卡抑制剂疗法构成了一种有前途的癌症治疗策略,其靶向免疫关卡重新激活沉默的T细胞细胞毒性。在最近的关键试验中,免疫检查点封锁(ICB)表现出持久的反应性和可接受的毒性,因此迄今为止,已有15种癌症适应症获得8种检查点抑制剂的监管批准。但是,约有85%的患者对ICB具有先天或后天抵抗力,从而限制了其临床实用性。当前反应生物标志物候选物,包括DNA突变和新抗原负荷,免疫谱以及程序性死亡配体1(PD-L1)表达,只是ICB反应的弱预测指标。因此,鉴定可以鉴定出将受益于ICB的患者的新颖,更具预测性的生物标记物是免疫疗法研究的最重要领域之一。在多种癌症中发现了异常的DNA甲基化(5mC)和羟甲基化(5hmC),并已在T细胞分化和激活过程中确定了表观基因组格局的动态变化。尽管它们在癌症免疫抑制中的作用仍有待阐明,但最近的证据表明5mC和5hmC可能是ICB敏感癌症的预后和预测生物标志物。在这篇综述中,我们描述了表观遗传现象在肿瘤免疫编辑和其他免疫逃避相关过程中的作用,提供了ICB反应生物标记物当前状态的全面更新,并突出了有前途的表观基因组生物标记物候选物。

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