Abstract
Despite Glioblastoma (GBM) frequently expressing programmed cell death ligand-1 (PD-L1), treatment with anti-programmed cell death-1 (PD1) has not yielded brilliant results. Intratumor variability of PD-L1 can impact determination accuracy. A previous study on mouse embryonic fibroblasts (MEFs) reported a role for cyclin-D in control of PD-L1 expression. Because tumor-cell growth within a cancer is highly heterogeneous, we looked at whether PD-L1 and its cochaperone FKBP51s were influenced by cell proliferation, using U251 and SF767 GBM-cell-lines. PD-L1 was measured by Western blot, flow cytometry, confocal-microscopy, quantitative PCR (qPCR), CCND1 by qPCR, FKBP51s by Western blot and confocal-microscopy. Chromatin-Immunoprecipitation assay (xChIp) served to assess the DNA-binding of FKBP51 isoforms. In the course of cell culture, PD-L1 appeared to increase concomitantly to cyclin-D on G1/S transition, to decrease during exponential cell growth progressively. We calculated a correlation between CCND1 and PD-L1 gene expression levels. In the temporal window of PD-L1 and CCND1 peak, FKBP51s localized in ER. When cyclin-D declined, FKBP51s went nuclear. XChIp showed that FKBP51s binds CCND1 gene in a closed-chromatin configuration. Our finding suggests that the dynamism of PD-L1 expression in GBM follows cyclin-D fluctuation and raises the hypothesis that FKBP51s might participate in the events that govern cyclin-D oscillation.
Highlights
PD-L1, known as CD274 or B7-H1, is a transmembrane protein physiologically expressed on the plasma membrane of antigen presenting cells and aberrantly expressed by tumor cells, supporting tumor immune evasion [1]
The epithelial to mesenchymal transition (EMT) state accounts for an acquired PD-L1 phenotype [3]
To provide more knowledge on PD-L1 expression in GBM, we investigated whether cyclin D and proliferation rates affected the expression levels of PD-L1 in GBM cell lines
Summary
PD-L1, known as CD274 or B7-H1, is a transmembrane protein physiologically expressed on the plasma membrane of antigen presenting cells and aberrantly expressed by tumor cells, supporting tumor immune evasion [1]. Genetic/epigenetic alterations, deregulated activation of oncogenic signaling pathways and stimuli from microenvironment [2] are among the causes of aberrant expression of such an immune modulatory ligand in cancer cells. The EMT state attracts immune cells [3] that play a crucial role in stimulation of PD-L1 expression through IFN-γ and the type II IFN receptor signaling pathway [4]. FKBP5 is among the top 10% highly expressed genes in GBM (www.oncomine.org (accessed on 20 April 2019)); it correlates with glioma tumor grading [6] and supports the glioma stem cell niche [7]. An IHC study on 29 GBM specimens showed that FKBP51s is broadly expressed in this tumor, albeit with different proportion/intensity scores, with nuclear and/or cytoplasmic localization [5]. FKBP51s cochaperone assists PD-L1 production in ER, and it becomes nuclear when cyclin D declines
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