de With Mirjam, Hurkmans Daan P, Oomen-de Hoop Esther, Lalouti Ayoub, Bins Sander, El Bouazzaoui Samira, van Brakel Mandy, Debets Reno, Aerts Joachim G J V, van Schaik Ron H N, Mathijssen Ron H J, van der Veldt Astrid A M
Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands.
Department of Clinical Chemistry, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands.
Cancers (Basel). 2021 Mar 18;13(6):1370. doi: 10.3390/cancers13061370.
A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were treated with pembrolizumab or nivolumab monotherapy, blood samples were genotyped for 11 SNPs in nine genes. Associations between SNPs and OS were tested using Cox regression analysis and internally validated by bootstrapping. For SNPs with a statistical significance, an expression quantitative trait loci (eQTL) analysis was performed. In a subset of patients, immunophenotyping was performed. Patients with a SNP in (804C > T; rs2227981) had a significantly poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients (hazard ratio [HR] 2.37; 95% CI: 1.11-5.04; = 0.026). eQTL analysis showed that this SNP was associated with decreased gene expression. In addition, 804C > T carriers had a reduced fraction of peripheral PD-1CD4 T cells. No other associations between SNPs and OS were found. 804C > T is associated with poorer OS after anti-PD-1 monotherapy in patients with metastatic melanoma. This SNP may affect clinical benefit from ICIs by decreasing transcription initiation and expression of PD-1 in T cells.
相当数量的黑色素瘤患者无法从抗PD-1治疗中获益。因此，我们研究了转移性黑色素瘤患者中与PD-1轴相关基因的单核苷酸多态性（SNP）的预测价值。从119例接受帕博利珠单抗或纳武利尤单抗单药治疗的连续黑色素瘤患者中，对9个基因中的11个SNP进行血液样本基因分型。使用Cox回归分析测试SNP与总生存期（OS）之间的关联，并通过自抽样进行内部验证。对于具有统计学意义的SNP，进行表达定量性状位点（eQTL）分析。在一部分患者中进行了免疫表型分析。携带（804C>T；rs2227981）SNP的患者OS明显较差，3年OS率为51.8%，而野生型患者为71%（风险比[HR]2.37；95%CI：1.11-5.04；P=0.026）。eQTL分析表明，该SNP与基因表达降低有关。此外，804C>T携带者外周血PD-1+CD4+T细胞比例降低。未发现其他SNP与OS之间的关联。804C>T与转移性黑色素瘤患者抗PD-1单药治疗后的较差OS相关。该SNP可能通过降低T细胞中PD-1的转录起始和表达来影响免疫检查点抑制剂（ICI）的临床获益。
