PD-L1 Expression is Mediated by microRNA Processing, Wnt/β-Catenin Signaling, and Chemotherapy in Wilms Tumor

  • Pediatr Blood Cancer. 2025 Sep;72(9):e31852. doi: 10.1002/pbc.31852.
Patricia D B Tiburcio  1 ,  Kavita Desai  2  3 ,  Austin Warne  1 ,  Arash Nabbi  4 ,  Serena Zhou  1 ,  Sean D Reiff  1 ,  Matthew E Campbell  1 ,  James F Amatruda  5  6  7 ,  Kenneth S Chen  1  8
Affiliations
  • 1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 2. University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
  • 3. Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 4. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 5. Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
  • 6. Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
  • 7. Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
  • 8. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
PMID: 40512079 DOI: 10.1002/pbc.31852
Abstract

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.

Keywords
immunotherapy; molecular genetics; wilms tumor.
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