PD-1/PD-L1阻断治疗的遗传生物标志物

K. Kataoka, S. Ogawa
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引用次数: 10

摘要

使用针对程序性细胞死亡1 (PD-1)和PD-1配体1 (PD-L1)的抗体的免疫检查点阻断疗法正在彻底改变癌症治疗(1-3)。这些抗体为各种类型的晚期癌症,如黑色素瘤、非小细胞肺癌、肾癌和霍奇金淋巴瘤患者提供长期持久的反应(1-3)。越来越多的证据表明,这些药物通过靶向PD-1/PD-L1免疫检查点来释放抗肿瘤免疫反应来传递其治疗效果。反过来,据推测,癌细胞主要依赖于逃避免疫监视其恶性生长。由于免疫检查点阻断疗法仅使一小部分患者受益,因此确定可以预测治疗疗效和不良反应的生物标志物非常重要,最近批准的PD-L1诊断测试证实了这一点(2)。在这里,我们简要概述了PD-1/PD-L1阻断疗法的遗传生物标志物的最新发展,特别关注PD-L1遗传异常,包括其3 ' -UTR中断。早期的研究表明,免疫生物标志物,如肿瘤内淋巴浸润和肿瘤或浸润性免疫细胞上的PD-L1表达,在预测对PD-1/PD-L1阻断治疗的反应方面具有潜在的价值(1,2)。然而,随后的研究显示,PD-L1肿瘤患者的应答率较低但显著,这引发了对这些免疫标志物作为PD-1/PD-L1阻断治疗的理想选择标准的实用性的质疑(2)。根据包括各种实体癌类型在内的15项研究的结果估计,PD-L1 +肿瘤患者对PD-1/PD-L1阻断的总有效率为48%,而PD-L1肿瘤患者的总有效率为15%。此外,特别是在临床环境中,PD-L1蛋白表达的准确测量和评分受到各种技术和生物学陷阱的阻碍(2)。基于基因组学的方法有可能补充免疫生物标志物。特别是,Rizvi等人证明,通过全外显子组测序检测到的非同义突变和新抗原的较高负荷与非小细胞肺癌(NSCLC)患者对抗pd -1抗体(pembrolizumab)的临床反应呈正相关。此外,候选的新抗原被实验验证使用高通量多重筛选,以鉴定新抗原特异性T细胞。在一个应答者中,新抗原特异性t细胞反应性与肿瘤消退平行(4)。除了新抗原负荷外,单个肿瘤内新抗原异质性(ITH)的程度影响对免疫调节的敏感性。对ITH和新抗原负荷的综合分析表明,在非小细胞肺癌患者中,富含克隆性新抗原的肿瘤对PD-1阻断的反应增强。
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Genetic biomarkers for PD-1/PD-L1 blockade therapy
Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment (1-3). These antibodies provide long-term durable responses for patients with various types of advanced cancers, such as melanoma, non–small-cell lung cancer, kidney cancer, and Hodgkin lymphoma (1-3). Accumulating evidence suggests that these agents convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash anti-tumor immune responses. In turn, it is supposed that cancer cells depend critically on evading immune surveillance for their malignant growth. As immune checkpoint blockade therapy has benefited only a subset of patients, defining biomarkers that can predict therapeutic efficacy and adverse effects is of urgent importance, which is substantiated by recent approvals for PD-L1 diagnostic tests (2). Here we provide a brief overview of the recent development of genetic biomarkers for PD-1/PD-L1 blockade therapies, with special focus on PD-L1 genetic abnormalities, including its 3′-UTR disruption. Early studies demonstrated the potential value of immunological biomarkers, such as intratumoral lymphoid infiltrates and PD-L1 expression on tumor or infiltrating immune cells, for predicting response to PD-1/PD-L1 blockade (1, 2). However, subsequent studies have revealed a lower but significant response rate in patients with PD-L1-tumors, raising questions about the utility of these immunological markers as an ideal selection criterion for PD-1/PD-L1 blockade therapy (2). Indeed, estimated from the results across 15 studies including various solid cancer types, the overall response rate to PD-1/PD-L1 blockade was 48% in patients with PD-L1 + tumors, in contrast to 15% in those with PD-L1-tumors. In addition, especially in clinical setting, accurate measurement and scoring of PD-L1 protein expression are hampered by a variety of technical and biological pitfalls (2). Genomics-based approaches have the potential to complement immunological biomarkers. In particular, Rizvi et al. demonstrated that a higher load of nonsynonymous mutations and neoantigens detected by whole-exome sequencing positively correlated with clinical response to an anti-PD-1 antibody (pembrolizumab) in non-small cell lung cancer (NSCLC) patients. Moreover, candidate neoantigens were experimentally validated using a high-throughput multimer screening to identify neoantigen-specific T cells. In one responder, neoantigen-specific T-cell reactivity paralleled tumor regression (4). In addition to neoantigen load, the extent of neoantigen intratumoral heterogeneity (ITH) within single tumors affects the sensitivity to immune modulation. An integrated analysis of ITH and neoantigen burden showed that the response to PD-1 blockade in patients with NSCLC was enhanced in tumors enriched for clonal neoantigens, i.e., those shared …
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