PD-L1 expression is mediated by microRNA processing, Wnt/β-catenin signaling, and chemotherapy in Wilms tumor

Abstract

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. Here, we show that PD-L1 is 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 childhood cancer cell lines 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/{beta}-catenin signaling and knockdown of DROSHA or DICER1 both increase PD-L1 in vitro. Lastly, in adult cancers, DICER1 alterations are associated with immune gene expression signatures and improved survival in response to immune checkpoint inhibitors. Together, our results identify clinical and biological properties regulating PD-L1 in Wilms tumor that may inform precision therapy approaches in pediatric immuno-oncology.