Il‐27 mediates pd‐l1 expression and release by human mesothelioma cells

Malignant mesothelioma (MM) is a rare tumor with an unfavorable prognosis. MM gen-esis 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 investi-gated 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 meas-ured 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 phos-phorylation 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.