Tiburcio Patricia D B, Desai Kavita, Warne Austin, Nabbi Arash, Zhou Serena, Reiff Sean D, Campbell Matthew E, Amatruda James F, Chen Kenneth S
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Pediatr Blood Cancer. 2025 Sep;72(9):e31852. doi: 10.1002/pbc.31852. Epub 2025 Jun 13.
Inhibition of immune checkpoint proteins is effective in adult cancers but has shown limited efficacy in pediatric cancers. While factors regulating expression of immune checkpoint proteins such as PD-L1 are well documented in adult cancers, their regulation is poorly understood in pediatric cancers.
We analyzed Wilms tumor specimens with reverse-phase protein arrays. We validated correlations using published sequencing data, flow cytometry, and immunoblots.
Using unsupervised clustering of protein arrays, we found that immune markers like PD-L1 are upregulated in distinct subsets of Wilms tumor, the most common pediatric kidney cancer. Specifically, chemotherapy-exposed Wilms tumor specimens exhibited higher levels of PD-L1 expression, and common chemotherapeutics upregulated PD-L1 in vitro. Furthermore, mutations in CTNNB1 and DROSHA, the two most commonly mutated genes in Wilms tumor, correlated with higher PD-L1. Activation of Wnt/β-catenin signaling and knockdown of DROSHA or DICER1 both increase PD-L1 in vitro.
Together, our results identify clinical and biological properties regulating PD-L1 in Wilms tumor that may inform precision therapy approaches in pediatric immuno-oncology.
免疫检查点蛋白的抑制在成人癌症中有效，但在儿童癌症中疗效有限。虽然在成人癌症中，调节免疫检查点蛋白（如PD-L1）表达的因素已有充分记录，但在儿童癌症中对其调节机制了解甚少。
我们使用反相蛋白质阵列分析了肾母细胞瘤标本。我们利用已发表的测序数据、流式细胞术和免疫印迹法验证了相关性。
通过对蛋白质阵列进行无监督聚类分析，我们发现免疫标志物如PD-L1在肾母细胞瘤（最常见的儿童肾癌）的不同亚组中上调。具体而言，接受化疗的肾母细胞瘤标本显示出更高水平的PD-L1表达，并且常见的化疗药物在体外上调了PD-L1。此外，肾母细胞瘤中两个最常发生突变的基因CTNNB1和DROSHA的突变与更高的PD-L1相关。Wnt/β-连环蛋白信号通路的激活以及DROSHA或DICER1的敲低在体外均增加了PD-L1。
总之，我们的研究结果确定了肾母细胞瘤中调节PD-L1的临床和生物学特性，这可能为儿童免疫肿瘤学的精准治疗方法提供依据。
