PD-L1 Expression is Mediated by microRNA Processing, Wnt/β-Catenin Signaling, and Chemotherapy in Wilms Tumor.
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BACKGROUND: 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. METHODS: We analyzed Wilms tumor specimens with reverse-phase protein arrays. We validated correlations using published sequencing data, flow cytometry, and immunoblots. RESULTS: 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. CONCLUSIONS: Together, our results identify clinical and biological properties regulating PD-L1 in Wilms tumor that may inform precision therapy approaches in pediatric immuno-oncology.