ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC
ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC
复制标题
ARID1A突变加CXCL13表达作为组合生物标志物预测mUCC对免疫检查点治疗的应答
DOI：
10.1126/scitranslmed.abc4220
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发表时间：
2020-06-17
影响因子：
17.1
通讯作者：
Sharma, Padmanee
中科院分区：
文献类型：
--
作者：
Goswami, Sangeeta;Chen, Yulong;Sharma, Padmanee
免疫检查点疗法（ICT）可以在转移性尿路上皮癌（mUCC）中产生持久的抗肿瘤反应；然而，这些反应并不是普遍的。尽管在mUCC中多次批准ICT，但我们缺乏预测性生物标志物来指导患者选择。生物标志物的鉴定可能需要询问肿瘤突变状态和免疫微环境。通过对基线肿瘤组织的多平台免疫基因组分析，我们发现肿瘤细胞中富含at的相互作用结构域蛋白1A （ARID1A）的突变和基线肿瘤组织中免疫细胞因子CXCL13的表达是临床反应的两个预测因素（n = 31）。此外，反向翻译研究显示，在膀胱癌小鼠模型中，CXCL13（-/-）荷瘤小鼠对ICT具有抗性，而ARID1A敲除增强了对ICT的敏感性。接下来，我们在两个独立的验证队列（CheckMate275和IMvigor210）中测试了ARID1A突变和CXCL13基线表达的临床相关性。我们发现，在两个验证性队列（CheckMate275， CXCL13数据，n = 217； ARID1A数据，n = 139; IMvigor210， CXCL13数据，n = 348； ARID1A数据，n = 275）中，基线肿瘤组织中ARID1A突变和CXCL13表达与总生存期（OS）的改善相关。然后，我们研究了CXCL13表达和ARID1A突变作为预测CheckMate275和IMvigor210对ICT反应的联合生物标志物。基线肿瘤组织中两种生物标志物的联合使用表明，与单一生物标志物相比，OS得到改善。综上所述，本研究表明CXCL13与ARID1A联合使用可提高接受ICT患者的预测能力。
Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ICT in mUCC, we lack predictive biomarkers to guide patient selection. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Through multi-platform immuno-genomic analyses of baseline tumor tissues, we identified the mutation of AT-rich interactive domain-containing protein 1A (ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the baseline tumor tissues as two predictors of clinical responses in a discovery cohort (n = 31). Further, reverse translational studies revealed that CXCL13(-/-) tumor-bearing mice were resistant to ICT, whereas ARID1A knockdown enhanced sensitivity to ICT in a murine model of bladder cancer. Next, we tested the clinical relevance of ARID1A mutation and baseline CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to ICT in CheckMate275 and IMvigor210. Combination of the two biomarkers in baseline tumor tissues suggested improved OS compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving ICT.