Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade
Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade
复制标题
DNA 损伤反应途径中的突变可作为免疫检查点阻断的潜在生物标志物
DOI：
10.1158/0008-5472.can-18-1814
复制
发表时间：
2018-11-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Jie
中科院分区：
文献类型：
--
作者：
Wang, Zhijie;Zhao, Jing;Wang, Jie
程序性死亡受体1配体（PD-L1）表达、肿瘤突变负荷（TMB）和高微卫星不稳定性等生物标志物可能适用于预测免疫检查点阻断（ICB）的疗效。然而，一些挑战，如定义的截止值，测试平台的一致性，和低频率限制了其广泛的临床应用。在此，我们鉴定了同源重组修复和错配修复（HRR-MMR）或HRR和碱基切除修复（HRR-BER;定义为co-mut（+））的DNA损伤反应（DDR）途径中的突变，这些突变与TMB和新抗原负荷增加以及免疫基因表达特征水平增加相关。在4个公共临床队列中，与共同mut（-）患者相比，共同mut（+）患者的客观缓解率更高，无进展生存期或总生存期更长。总体而言，鉴别HRR-MMR或HRR-BER中的DDR comutations作为ICB应答的预测因子为未来的临床实践提供了一种潜在的方便方法。意义：鉴别特定DDR通路中的comutations作为免疫检查点阻断应答的上级生存结局的预测因子，为估计肿瘤突变负荷和ICB治疗的递送提供了一种临床上方便的方法。(C)2018年AACR。
Biomarkers such as programmed death receptor 1 ligand (PD-L1) expression, tumor mutational burden (TMB), and high microsatellite instability are potentially applicable to predict the efficacy of immune checkpoint blockade (ICB). However, several challenges such as defining the cut-off value, test platform uniformity, and low frequencies limit their broad clinical application. Here we identify comutations in the DNA damage response (DDR) pathways of homologous recombination repair and mismatch repair (HRR-MMR) or HRR and base excision repair (HRR-BER; defined as co-mut(+)) that are associated with increased TMB and neoantigen load and increased levels of immune gene expression signatures. In four public clinical cohorts, co-mut(+) patients presented a higher objective response rate and a longer progression-free survival or overall survival than co-mut(-) patients. Overall, identification of DDR comutations in HRR-MMR or HRR-BER as predictors of response to ICB provides a potentially convenient approach for future clinical practice.Significance: Identification of comutations in specific DDR pathways as predictors of superior survival outcomes in response to immune checkpoint blockade provide a clinically convenient approach for estimation of tumor mutational burden and delivery of ICB therapy. (C) 2018 AACR.