Raimondi Alessandra, Sepe Pierangela, Zattarin Emma, Mennitto Alessia, Stellato Marco, Claps Melanie, Guadalupi Valentina, Verzoni Elena, de Braud Filippo, Procopio Giuseppe
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy.
Front Oncol. 2020 Aug 12;10:1644. doi: 10.3389/fonc.2020.01644. eCollection 2020.
In the last decades, the therapeutic decision-making approach to metastatic renal cell cancer (mRCC) has dramatically changed thanks to the introduction in the treatment scenario of, first, anti-angiogenic agents and, afterward, immune-checkpoint inhibitors (ICIs). Immunotherapy is now the standard of care in pretreated mRCC patients and has recently entered even the first line setting. Nevertheless, in mRCC as well as in other tumor settings, a durable and clinically meaningful benefit from treatment with ICIs is not obtained for all patients treated. Therefore, the necessity to identify and validate predictive biomarkers of response to immunotherapy has emerged, in order to design the optimal treatment strategy for mRCC patients.
In this review, we present and discuss the most promising predictive biomarkers of response to ICIs in mRCC with the recent data available. In details, the first marker that was investigated is the immunohistochemical expression of programmed death receptor ligand 1 (PD-L1), showing a negative prognostic role in mRCC, but the debate about its potential predictive value is still open. Additionally, the high heterogeneity in PD-L1 determination methods adds complexity to this issue. Second, the tumor mutational or neoantigen burden is an emerging biomarker of increased response to immunotherapy, hypothesizing that the higher the TMB, the higher is the production of neoantigens, and thus the stimulation of anti-tumor immune response, even though controversial results have been obtained. Third, the tumor microenvironment, namely the different populations of the immune infiltrate, plays a key role in tumor progression and in the response to immunotherapy. Finally, several studies have collected evidence on the potential association of the occurrence of immune-related adverse events (irAEs) with the benefit from ICIs, first in non-small cell lung cancer (NSCLC) and melanoma, and recently even in mRCC.
Several promising biomarkers of response to immunotherapy with ICIs have been identified, though without conclusive results upon their potential predictive value in mRCC. Therefore, the results of the exploratory analyses of the recently presented first-line trials and hopefully of future prospective, biomarker-driven studies could provide useful tools to be applied in the everyday clinical practice.
在过去几十年中，转移性肾细胞癌（mRCC）的治疗决策方法发生了巨大变化，这得益于治疗方案中首先引入抗血管生成药物，随后引入免疫检查点抑制剂（ICI）。免疫疗法现在是预处理mRCC患者的标准治疗方法，最近甚至进入了一线治疗领域。然而，在mRCC以及其他肿瘤环境中，并非所有接受治疗的患者都能从ICI治疗中获得持久且具有临床意义的益处。因此，为了为mRCC患者设计最佳治疗策略，识别和验证免疫治疗反应预测生物标志物的必要性应运而生。
在本综述中，我们根据现有最新数据，介绍并讨论mRCC中对ICI反应最有前景的预测生物标志物。具体而言，首先研究的标志物是程序性死亡受体配体1（PD-L1）的免疫组化表达，其在mRCC中显示出负面预后作用，但关于其潜在预测价值的争论仍在继续。此外，PD-L1测定方法的高度异质性增加了这个问题的复杂性。其次，肿瘤突变或新抗原负荷是免疫治疗反应增加的新兴生物标志物，推测肿瘤突变负荷（TMB）越高，新抗原产生越多，从而刺激抗肿瘤免疫反应，尽管已获得有争议的结果。第三，肿瘤微环境，即免疫浸润的不同群体，在肿瘤进展和免疫治疗反应中起关键作用。最后，多项研究收集了证据，证明免疫相关不良事件（irAE）的发生与ICI获益之间存在潜在关联，首先是在非小细胞肺癌（NSCLC）和黑色素瘤中，最近甚至在mRCC中也有发现。
已经确定了几种有前景的ICI免疫治疗反应生物标志物，尽管关于它们在mRCC中的潜在预测价值尚无定论。因此，最近公布的一线试验探索性分析结果，以及有望开展的未来前瞻性、生物标志物驱动研究的结果，可能会提供可应用于日常临床实践的有用工具。
