文章：

肿瘤拷贝数变异负荷作为不同癌症类型中免疫检查点阻断耐药的预测因子

Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types

原文发布日期：9 February 2024

DOI: 10.3390/cancers16040732

类型: Article

开放获取: 是

英文摘要：

Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (n= 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (n= 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01–2.30),p= 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which “LowTMB/HighCNA” showed the worst survival (p< 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies.

摘要翻译： 

免疫检查点阻断疗法仅能使部分晚期癌症患者获益，因此需要寻找能够预测免疫治疗反应的生物标志物。近期研究提出拷贝数变异负荷可作为预测免疫检查点阻断耐药的指标。我们利用1661例接受免疫检查点阻断治疗患者的公开数据验证这一发现，所有肿瘤样本均采用临床获批的靶向检测技术MSK-IMPACT进行分析。我们验证了以下假设：拷贝数变异负荷的持续升高与免疫检查点阻断治疗后总生存期缩短相关；同时提出肿瘤突变负荷与拷贝数变异负荷的组合生物标志物能更有效区分患者的免疫状态及免疫检查点阻断治疗反应。在1661例病例中，79%（n=1307）接受抗PD-1/PD-L1治疗，其余21%（n=354）接受抗CTLA-4或联合治疗。多变量分析显示，拷贝数变异负荷升高与总生存期缩短显著相关[风险比=1.52，95%置信区间(1.01–2.30)，p=0.04]。肿瘤突变负荷与拷贝数变异负荷组合将患者分为四个临床特征各异的亚组，其中"低肿瘤突变负荷/高拷贝数变异负荷"亚组生存期最短（p<0.0001）。这四个亚组具有独特的拷贝数变异谱和富集通路，可预测肿瘤微环境中免疫信号传导及CD8+ T细胞丰度相关的转录组学与表型效应。研究表明，拷贝数变异负荷与免疫检查点阻断患者总生存期缩短相关，且与肿瘤突变负荷联合应用可优化患者分层。这些发现或将为免疫治疗患者筛选及替代治疗方案制定提供指导。

原文链接：

Tumor Copy Number Alteration Burden as a Predictor for Resistance to Immune Checkpoint Blockade across Different Cancer Types