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Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

机译：免疫检查点封闭反应的遗传和表观遗传生物标志物

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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.
机译：检查点抑制剂治疗构成有前途的癌症治疗策略，其靶向免疫检查点以重新激活沉默的T细胞细胞毒性。在最近的枢轴试验中，免疫检查点封锁（ICB）证明了持久的反应和可接受的毒性，导致8个检查点抑制剂的调节批准，迄今为止15例癌症适应症。但是，高达85％的患者患有先天或获得ICB的抗性，限制其临床效用。当前响应生物标志物候选者，包括DNA突变和新抗原载荷，免疫分布，以及编程的死亡配体1（PD-L1）表达仅是ICB响应的弱预测因子。因此，鉴定新的，更具预测的生物标志物，可以识别将从ICB受益的患者构成免疫治疗研究中最重要的领域之一。在多种癌症中发现异常DNA甲基化（5MC）和羟甲基化（5HMC），并且在T细胞分化和活化期间已经鉴定了表观态景观的动态变化。虽然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可以作为ICB敏感癌症的预后和预测生物标志物。在本综述中，我们描述了表观遗传现象在肿瘤免疫的作用和其他免疫逃避相关过程中，提供了综合了解ICB响应生物标志物的现状，并突出了有前列的表观胶质生物标志物候选者。

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