Abstract
Gliomas aberrantly express programmed cell death ligand-1 (PD-L1), which has a pivotal role in immunoevasion. The splicing isoform of FKBP5, termed FKBP51s, is a PD-L1 foldase, assisting the immune checkpoint molecule in maturation and expression on the plasma membrane. The concept that PD-L1 supports tumor-intrinsic properties is increasingly emerging. The aim of the present work was to confirm the pro-tumoral effect of PD-L1 on human glioma cell survival, stemness capacity and resistance, and to address the issue of whether, by targeting its foldase either chemically or by silencing, the aggressive tumor features could be attenuated. PD-L1-depleted glioma cells have a reduced threshold for apoptosis, while PD-L1 forced expression increases resistance. Similar results were obtained with FKBP51s modulation. The ability of PD-L1 to counteract cell death was hampered by FKBP51s silencing. PD-L1 expression was particularly high in glioma cells with a cancer-stem-cell profile. Moreover, PD-L1 sustained the spheroid formation capability of glioma cells. Targeting of FKBP51s by small-interfering RNA (siRNA) or the specific inhibitor SAFit2, reduced the number of formed spheroids, along with PD-L1 expression. Finally, in an orthotopic mouse model of glioblastoma, daily treatment with SAFit2 significantly reduced tumor PD-L1 expression, and tumor growth. In treated mice, caspase-3 activation and reduced vimentin expression were observed in excised tumors. In conclusion, targeting of FKBP51s hampers PD-L1 and its pro-tumoral properties, thereby affecting the self-renewal and growth capacities of glioblastoma cells in vitro and in vivo.
Highlights
Glioblastoma multiforme (GBM) is the most common, and the most dangerous and aggressive form of Official journal of the Cell Death Differentiation AssociationD’Arrigo et al Cell Death Discovery (2019)5:137Several studies are in progress, especially exploring the combination of anti-programmed cell death-1 (PD-1) antibodies with chemotherapies or targeted therapies[6]
programmed cell death ligand-1 (PD-L1) promotes apoptosis resistance We investigated the effect of PD-L1 silencing on GBM
For PDL1 downmodulation, cells were treated with specific small-interfering RNA (siRNA) targeting PD-L1 or its co-chaperone FKBP51s
Summary
Glioblastoma multiforme (GBM) is the most common, and the most dangerous and aggressive form of Official journal of the Cell Death Differentiation AssociationD’Arrigo et al Cell Death Discovery (2019)5:137Several studies are in progress, especially exploring the combination of anti-PD-1 antibodies with chemotherapies or targeted therapies[6]. Glioblastoma multiforme (GBM) is the most common, and the most dangerous and aggressive form of Official journal of the Cell Death Differentiation Association. In addition to its immunomodulatory function, PD-L1 conveys a survival signal to the cancer cell and sustains tumor aggressiveness[6]. Azuma et al.[8] found that PD-L1, upon ligand stimulation, acts as a receptor that transduces pro-survival signals that enhance the threshold for apoptosis induced by both immune effectors and proapoptotic drugs. Qiu et al.[10] demonstrated that PD-L1 binds to Ras and activates the Ras/Erk pathway. Via this mechanism, PD-L1 promotes the epithelial-to-mesenchymal transition (EMT) and GBM cell migration
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