Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
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DOI：
10.1038/s41591-019-0654-5
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发表时间：
2019-12-01
期刊：
影响因子：
82.9
通讯作者：
Schadendorf, Dirk
中科院分区：
文献类型：
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作者：
Liu, David;Schilling, Bastian;Schadendorf, Dirk
免疫检查点阻断(ICB)已在许多肿瘤类型中显示出疗效，但对抗PD1 ICB应答的预测指标尚不完全确定。在这项研究中，我们分析了一组有临床注释的黑色素瘤患者(n=144)，接受了抗PD1 ICB治疗，并对治疗前的肿瘤进行了全外显子组和全转录组测序。我们发现，黑色素瘤亚型混淆了作为反应预测因子的肿瘤突变负荷，而多种新的基因组和转录学特征预测选择性反应，包括与MHC-I和MHC-II抗原呈递相关的特征。此外，与对ICB不敏感的肿瘤相比，先前的抗CTLA4 ICB暴露与不同的反应预测因子相关，提示先前暴露于抗CTLA4 ICB的选择性免疫效应。最后，我们开发了整合了临床、基因组和转录学特征的简约模型来预测个体肿瘤对抗PD1 ICB的内在耐药性，在较小的独立队列中的验证受到全面数据可用性的限制。概括地说，我们提出了一个框架来发现ICB治疗反应的预测特征并建立模型。
Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.