Ayers Mark, Lunceford Jared, Nebozhyn Michael, Murphy Erin, Loboda Andrey, Kaufman David R, Albright Andrew, Cheng Jonathan D, Kang S Peter, Shankaran Veena, Piha-Paul Sarina A, Yearley Jennifer, Seiwert Tanguy Y, Ribas Antoni, McClanahan Terrill K
Merck & Co. Inc., Kenilworth, New Jersey, USA.
University of Washington, Seattle, Washington, USA.
J Clin Invest. 2017 Aug 1;127(8):2930-2940. doi: 10.1172/JCI91190. Epub 2017 Jun 26.
Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ 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-γ-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.
程序性死亡-1导向（PD-1导向）的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，IFN-γ是癌症和宿主细胞中程序性死亡配体-1（PD-L1）表达的关键驱动因素，基线肿瘤内T细胞浸润可能会提高对抗PD-1疗法（包括帕博利珠单抗）的反应可能性。然而，量化T细胞炎性微环境是否是PD-1导向治疗反应的有用的泛肿瘤决定因素尚未得到严格评估。在此，我们使用帕博利珠单抗治疗患者的基线肿瘤样本中的RNA分析了基因表达谱（GEP）。我们基于帕博利珠单抗不同临床研究的数据，采用学习并确认的范式，从19例黑色素瘤患者的小型试点研究开始，最终在220例患有9种癌症的患者中定义了泛肿瘤T细胞炎性GEP，确定了与临床获益相关的免疫相关特征。在96例头颈部鳞状细胞癌患者中独立确认了预测价值，并与PD-L1免疫组化的预测价值进行了比较。T细胞炎性GEP包含与抗原呈递、趋化因子表达、细胞毒性活性和适应性免疫抵抗相关的IFN-γ反应基因，这些特征对于临床获益是必要的，但并不总是充分的。T细胞炎性GEP已发展成为一种临床级检测方法，目前正在正在进行的帕博利珠单抗试验中进行评估。
