Kovács Szonja Anna, Kovács Tamás, Lánczky András, Paál Ágnes, Hegedűs Zsombor I, Sayour Nabil V, Szabó Lilla, Kovács Andrea, Bianchini Giampaolo, Ferdinandy Péter, Ocana Alberto, Varga Zoltán V, Fekete János Tibor, Győrffy Balázs
Department of Bioinformatics, Semmelweis University, Budapest, Hungary.
Oncology Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
Br J Pharmacol. 2025 Aug;182(16):3903-3922. doi: 10.1111/bph.70052. Epub 2025 May 5.
Immune checkpoint inhibitors, such as anti-PD1, revolutionized melanoma treatment. However, resistance and low response rates remain problems. Our goal was to pinpoint actionable biomarkers of resistance to anti-PD1 treatment and verify therapeutic effectiveness in vivo.
Using receiver operating characteristic (ROC) and survival analysis in a database of 1434 samples, we identified the strongest resistance-associated genes. Inhibitors were evaluated in C57BL/6J mice using wild-type B16-F10, and BRAF, -PTEN, -CDKN2A-mutant YUMM1.7 melanoma cell lines. We investigated the synergistic impact of anti-PD1 therapy and yes-associated protein 1 (YAP1) inhibition by non-photoactivated Verteporfin. Tumour volume was determined at fixed cutoff points, normalized to body weights.
In the anti-PD1-treated melanoma cohort, YAP1 was the strongest druggable candidate overexpressed in non-responder patients (ROC AUC = 0.699, FC = 1.8, P=1.1E-8). The baseline YAP1 expression correlated with worse progression-free survival (HR = 2.51, P=1.2E-6, FDR = 1%), and overall survival (HR = 2.15, P = 1.2E-5, FDR = 1%). In YUMM1.7, combination of Verteporfin plus anti-PD1 reduced tumour size more than anti-PD1 monotherapy (P=0.008), or control (P=0.021). There was no difference between the cohorts in B16-F10 inoculated mice. We found increased expression of YAP1 in YUMM1.7 mice compared to B16-F10. The combination therapy induced a more-immune-inflamed phenotype characterized by increased expression of T cell and M1 macrophage markers.
Verteporfin with anti-PD1 exhibited antitumor potential by promoting a pro-inflammatory tumour microenvironment in melanoma. We believe that YAP1 acts as a master regulator of anti-PD1 resistance.
免疫检查点抑制剂，如抗程序性死亡蛋白1（anti-PD1），彻底改变了黑色素瘤的治疗方式。然而，耐药性和低反应率仍然是问题。我们的目标是确定抗PD1治疗耐药的可操作生物标志物，并在体内验证治疗效果。
在一个包含1434个样本的数据库中，使用受试者工作特征（ROC）和生存分析，我们确定了最强的耐药相关基因。使用野生型B16-F10以及BRAF、PTEN、CDKN2A突变的YUMM1.7黑色素瘤细胞系，在C57BL/6J小鼠中评估抑制剂。我们研究了抗PD1治疗与通过非光活化维替泊芬抑制Yes相关蛋白1（YAP1）的协同作用。在固定的时间点测定肿瘤体积，并根据体重进行标准化。
在接受抗PD1治疗的黑色素瘤队列中，YAP1是在无反应患者中过表达的最强可药物化候选物（ROC曲线下面积[AUC]=0.699，倍数变化[FC]=1.8，P=1.1×10⁻⁸）。YAP1的基线表达与更差的无进展生存期（风险比[HR]=2.51，P=1.2×10⁻⁶，错误发现率[FDR]=1%）和总生存期（HR=2.15，P=1.2×10⁻⁵，FDR=1%）相关。在YUMM1.7细胞系中，维替泊芬联合抗PD1比抗PD1单药治疗（P=0.008）或对照（P=0.021）更能减小肿瘤大小。在接种B16-F10的小鼠队列之间没有差异。我们发现与B16-F10相比，YUMM1.7小鼠中YAP1的表达增加。联合治疗诱导了一种更具免疫炎症的表型，其特征是T细胞和M1巨噬细胞标志物的表达增加。
维替泊芬与抗PD1联合使用通过促进黑色素瘤中促炎性肿瘤微环境展现出抗肿瘤潜力。我们认为YAP1是抗PD1耐药的主要调节因子。
