Abstract
Simple SummaryMalignant 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.
Highlights
Malignant mesothelioma (MM) is a rare tumor arising from the mesothelial cells underlining the pleural, peritoneal, or, less frequently, pericardial cavities
Since PD-L1 expression in mesothelioma cells is induced by IFN-γ vitro, we investigated the possible correlation between sPD-L1 and IFN-γ concentrations in pleural fluids in our patients’ cohort
In a previous study, we showed that IL-27, a cytokine produced by macrophages or DCs, may provide an alternative stimulus for PD-L1 expression in different types of human cancer cells [40]
Summary
Malignant mesothelioma (MM) is a rare tumor arising from the mesothelial cells underlining the pleural, peritoneal, or, less frequently, pericardial cavities. Immunotherapy with the anti-CTLA-4 mAb tremelimumab has shown no impact on survival when administered as a second- or third-line therapy in MM patients [2]. Immunotherapy with anti-PD-1 or anti-PD-L1 mAbs alone or in combination with anti-CTLA-4 mAbs showed promising activity in relapsing MM patients [3,4,5,6,7,8,9]. A recent phase III study showed that the combination of nivolumab and ipilimumab improved overall survival versus standard-of-care chemotherapy in unresectable MM [10]. These data support a role for the PD-1/PD-L1 interaction as a clinically relevant immune-suppressive mechanism in MM. High PD-L1 expression in MM tissues correlates with a more severe prognosis [11,12]
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