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PD-L1 Expression is Mediated by microRNA Processing, Wnt/β-Catenin Signaling, and Chemotherapy in Wilms Tumor
Patricia D B Tiburcio1, Kavita Desai2,3, Austin Warne1
1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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.
Insights
Immune checkpoint protein PD-L1 is upregulated in Wilms tumor subsets, particularly after chemotherapy. Mutations in CTNNB1 and DROSHA also correlate with higher PD-L1, informing pediatric cancer therapy.
Area of Science:
- Oncology
- Immunology
- Pediatric Research
Background:
- Immune checkpoint inhibition shows limited success in pediatric cancers compared to adult cancers.
- Regulation of immune checkpoint proteins like PD-L1 is poorly understood in pediatric malignancies.
Purpose of the Study:
- To investigate the regulation of PD-L1 expression in Wilms tumor, the most common pediatric kidney cancer.
- To identify clinical and biological factors associated with PD-L1 upregulation in pediatric cancers.
Main Methods:
- Analysis of Wilms tumor specimens using unsupervised clustering of reverse-phase protein arrays.
- Validation of findings using published sequencing data, flow cytometry, and immunoblots.
- In vitro experiments assessing PD-L1 regulation by chemotherapeutics, Wnt/β-catenin signaling, and gene knockdown (DROSHA, DICER1).
Main Results:
- PD-L1 is upregulated in distinct subsets of Wilms tumor.
- Chemotherapy exposure and common chemotherapeutics increase PD-L1 expression in vitro.
- Mutations in CTNNB1 and DROSHA, along with Wnt/β-catenin activation and DROSHA/DICER1 knockdown, correlate with or increase PD-L1 levels.
Conclusions:
- Clinical and biological factors regulating PD-L1 in Wilms tumor have been identified.
- These findings may guide the development of precision therapy strategies in pediatric immuno-oncology.
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