IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade
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DOI：
10.1172/jci91190
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发表时间：
2017-08-01
影响因子：
15.9
通讯作者：
McClanahan, Terrill K.
中科院分区：
文献类型：
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作者：
Ayers, Mark;Lunceford, Jared;McClanahan, Terrill K.
程序性死亡-1定向(PD-1-定向)免疫检查点阻断在许多晚期恶性肿瘤中产生持久的抗肿瘤活性。最近的研究表明，干扰素-γ是程序性死亡配体-1(PD-L1)在肿瘤和宿主细胞中表达的关键驱动因素，基线肿瘤内T细胞的浸润可能会提高包括培溴利珠单抗在内的抗PD-1治疗的应答可能性。然而，量化T细胞炎症的微环境是否是PD-1导向治疗反应的有用的泛肿瘤决定因素还没有得到严格的评估。在这里，我们使用pembrolizumab治疗患者的基线肿瘤样本的RNA来分析基因表达谱(GEP)。我们使用学习和确认范式确定了与临床益处相关的免疫相关信号，该范式基于对pembrolizumab的不同临床研究的数据，从19名黑色素瘤患者的小规模试验开始，最终在220名9种癌症的患者中定义了泛肿瘤T细胞炎症的GEP。并与PD-L1免疫组织化学方法在96例头颈部鳞状细胞癌患者中的预测价值进行比较。T细胞炎症的GEP含有与抗原提呈、趋化因子表达、细胞毒活性和获得性免疫抵抗相关的干扰素-γ反应基因，这些特征对于临床益处是必要的，但并不总是充分的。T细胞炎症的GEP已经开发成临床级别的测试，目前正在进行Pembrolizumab试验。
Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-gamma is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-gamma-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.