Rajakumar Timothy, Horos Rastislav, Jehn Julia, Schenz Judith, Muley Thomas, Pelea Oana, Hofmann Sarah, Kittner Paul, Kahraman Mustafa, Heuvelman Marco, Sikosek Tobias, Feufel Jennifer, Skottke Jasmin, Nötzel Dennis, Hinkfoth Franziska, Tikk Kaja, Daniel-Moreno Alberto, Ceiler Jessika, Mercaldo Nathaniel, Uhle Florian, Uhle Sandra, Weigand Markus A, Elshiaty Mariam, Lusky Fabienne, Schindler Hannah, Ferry Quentin, Sauka-Spengler Tatjana, Wu Qianxin, Rabe Klaus F, Reck Martin, Thomas Michael, Christopoulos Petros, Steinkraus Bruno R
Hummingbird Diagnostics GmbH, Im Neuenheimer Feld 583, 69120, Heidelberg, Germany.
Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
NPJ Precis Oncol. 2022 Mar 31;6(1):19. doi: 10.1038/s41698-022-00262-y.
Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune-related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only ~30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction. We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well-characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37-4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signaling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining.
免疫疗法最近已成为晚期癌症亚组中的高效疗法。不幸的是，只有少数患者能从免疫疗法中显著获益，而其他患者则无反应，甚至因免疫相关不良事件而受到伤害。对于PD-1/PD-L1抑制剂类免疫疗法，目前使用肿瘤（基于组织）的PD-L1表达进行患者分层。然而，PD-L1仅在约30%的病例中是反应的准确预测指标。迫切需要更准确的生物标志物来预测免疫治疗反应。我们试图基于全血微小RNA谱鉴定预测肺癌免疫治疗反应的外周血生物标志物。使用三个特征明确的队列，共334例IV期非小细胞肺癌患者，我们定义了一个5微小RNA风险评分（miRisk），该评分可预测训练和独立验证队列中免疫治疗后的总生存期（HR 2.40，95%CI 1.37 - 4.19；P < 0.01）。我们已将该特征追溯到髓系起源，并进行了miRNA靶点预测，以直接建立与PD-L1信号通路和PD-L1本身的机制联系。miRisk评分提供了一种潜在的基于血液的免疫治疗伴随诊断方法，其性能优于基于组织的PD-L1染色。
