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IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells
Grazia Carbotti1, Beatrice Dozin2, Stefania Martini3
1Biotherapies Unit, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genoa, Italy.
Abstract:
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.
Insights
Interleukin-27 (IL-27) significantly increases PD-L1 expression in malignant mesothelioma (MM) cells, potentially driving immune resistance. IL-27 in patient pleural fluid correlates with poorer survival and higher soluble PD-L1 levels.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Malignant mesothelioma (MM) is a rare, aggressive cancer linked to asbestos exposure.
- Inflammation, involving cytokines like IL-6, plays a role in MM development.
- Immune checkpoint inhibitors targeting PD-1/PD-L1 show therapeutic promise in MM.
Purpose of the Study:
- To investigate the impact of IL-6 trans-signaling and IL-27 on human MM cells.
- To assess the effects on PD-L1 expression and release of soluble PD-L1 (sPD-L1).
- To correlate IL-6, IL-27, and sPD-L1 levels in patient pleural fluid with survival outcomes.
Main Methods:
- Western blot analysis of STAT1/3 phosphorylation.
- Quantitative real-time PCR (qRT-PCR) and flow cytometry for PD-L1 expression.
- Enzyme-linked immunosorbent assay (ELISA) for sPD-L1.
- Multiplexed immunoassay for IL-6 and IL-27 in patient pleural fluid.
Main Results:
- IL-27 significantly increased PD-L1 gene and surface protein expression and sPD-L1 release in MM cells.
- IL-6 showed limited effects, and a chimeric IL-6 protein primarily activated STAT3 without affecting PD-L1.
- Elevated IL-6, IL-27, and sPD-L1 were found in pleural fluids, correlating negatively with overall survival.
Conclusions:
- IL-27 plays a significant role in enhancing PD-L1 expression and sPD-L1 release in MM.
- IL-27, but not IL-6 trans-signaling, influences PD-L1 pathways in MM cells.
- These findings suggest IL-27's potential role in PD-L1-mediated immune resistance in malignant mesothelioma.
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