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- Title
IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells.
- Authors
Carbotti, Grazia; Dozin, Beatrice; Martini, Stefania; Giordano, Chiara; Scordamaglia, Francesca; Croce, Michela; Filaci, Gilberto; Ferrini, Silvano; Fabbi, Marina
- Abstract
Simple Summary: Malignant mesothelioma (MM), a rare and aggressive tumor, is related to asbestos exposure, which mediates a chronic inflammatory process involving the cytokine IL-6. Recent studies indicate that the PD-1/PD-L1 immune-suppressive axis is a clinically relevant target for therapy. The expression of PD-L1 in tumor cells is generally a cytokine-mediated effect. Here we show that the IL-6-related cytokine IL-27 is able to enhance PD-L1 expression and soluble (s)PD-L1 release by cultured MM cells, whereas IL-6 is ineffective. In agreement with previous findings, we found high IL-6 levels in pleural exudates from 77 MM patients which correlated with worse survival. More importantly, we also found sPD-L1 and IL-27 in the same samples. sPD-L1 and IL-27 levels showed a moderate albeit significant correlation and association with worse survival, which suggested a potential effect of IL-27 on PD-L1-mediated immune resistance in MM. Malignant mesothelioma (MM) is a rare tumor with an unfavorable prognosis. MM genesis involves asbestos-mediated local inflammation, supported by several cytokines, including IL-6. Recent data showed that targeting PD-1/PD-L1 is an effective therapy in MM. Here, we investigated the effects of IL-6 trans-signaling and the IL-6-related cytokine IL-27 on human MM cells in vitro by Western blot analysis of STAT1/3 phosphorylation. The effects on PD-L1 expression were tested by qRT-PCR and flow-cytometry and the release of soluble (s)PD-L1 by ELISA. We also measured the concentrations of sPD-L1 and, by multiplexed immunoassay, IL-6 and IL-27 in pleural fluids obtained from 77 patients in relation to survival. IL-27 predominantly mediates STAT1 phosphorylation and increases PD-L1 gene and surface protein expression and sPD-L1 release by human MM cells in vitro. IL-6 has limited activity, whereas a sIL-6R/IL-6 chimeric protein mediates trans-signaling predominantly via STAT3 phosphorylation but has no effect on PD-L1 expression and release. IL-6, IL-27, and sPD-L1 are present in pleural fluids and show a negative correlation with overall survival, but only IL-27 shows a moderate albeit significant correlation with sPD-L1 levels. Altogether these data suggest a potential role of IL-27 in PD-L1-driven immune resistance in MM.
- Subjects
INTERLEUKINS; CYTOKINES; STAT proteins; MESOTHELIOMA; REVERSE transcriptase polymerase chain reaction; IN vitro studies; FLOW cytometry; PLEURAL effusions; WESTERN immunoblotting; CELL physiology; CELLULAR signal transduction; GENE expression; IMMUNOASSAY; SURVIVAL analysis (Biometry); ENZYME-linked immunosorbent assay; MEMBRANE proteins; POLYMERASE chain reaction; PHOSPHORYLATION
- Publication
Cancers, 2021, Vol 13, Issue 16, p4011
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13164011