Growth and differentiation factor 15 regulates PD-L1 expression in glioblastoma

Background: Gliomablastoma multiforme (GBM) is the most fatal form of all brain cancers in human with no successful treatment available. Programmed death-ligand 1 (PD-L1) is a coinhibitory ligand predominantly expressed by tumor cells. Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in tissue development and cancer. Purpose: To investigat the expression of GDFs in GBMs, and explored the potential regulatory role of GDFs on PD-L1 expression in GBMs. Methods: GEO2R program were analyzed for the mRNA expression data of GDFs in GSE4290 dataset. Analysis of TCGA GBM datasets were further determined the relationship between GDFs and PD-L1. Western blot Western blot was used to detect the expression of PD-L1 in GBM cell lines. Results: GDFs displayed differential patterns of expression with GDF15 and myostatin (MSTN) highly enriched in GBM tissues. We also identified GDF15 as a novel regulator that induces PD-L1 expression in GBM cells. Consistently, GDF15 expression correlated with PD-L1 in TCGA GBM dataset. Further, GDF15 enhanced PD-L1 expression via Smad2/3 pathway in GBM cell line U87, U251 and SHG44, which was inhibited by Smad2/3 inhibitor SIS3. Knockdown of GDF15 attenuated Smad2/3 signaling and reduced PD-L1 expression in A172 and GIC6 glioma cells. Conclusion: GDF15 might be a novel regulator of PD-L1 expression in GBMs; targeting GDF15/PD-L1 pathway might be a promising therapeutic approach for GBM patients.