IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells

Our plain-English summary of IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells, by G. Carbotti, B. Dozin, S. Martini, et al (Cancers, 2021).

The study

• Authors: G. Carbotti, B. Dozin, S. Martini, C. Giordano, F. Scordamaglia, M. Croce, G. Filaci, S. Ferrini, M. Fabbi
• Journal: Cancers
• Published: 2021;13(16)
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study tested how the immune signaling protein IL-27, and the related IL-6, affected three human malignant mesothelioma (MM) cell lines. It focused on PD-L1, a molecule tumors can use to dampen immune attack. IL-27 raised surface PD-L1 about three-fold on average across the three cell lines and increased soluble PD-L1 release from two of them. IL-6 and a lab-made IL-6 complex did not. The authors measured these molecules in stored pleural fluid from 77 MM patients, taken July 2012 to July 2019. Patients with higher IL-27 were more likely to have high soluble PD-L1 (odds ratio 4.86, 95% CI 1.86–12.79). Median survival, counted from fluid collection, was 10.4 months (95% CI 8.0–12.8). Higher soluble PD-L1 and higher IL-6 were linked with shorter survival. Higher IL-27 was not significantly linked to survival in the whole group (p = 0.111), but was among the 55 patients with epithelioid tumors (p = 0.009). Patients' asbestos exposure was not reported. The authors concluded that IL-27 may play an immune regulatory role in advanced-stage MM, possibly through inducing PD-L1.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments on human mesothelioma cell lines, combined with measurement of molecules in stored pleural fluid samples from patients and analysis of their survival
• Who was studied: Three human MM cell lines (MSTO, MPP89, IST-MES1). Pleural effusion samples from 77 MM patients from the Alessandria Biobank (Alessandria, Italy), taken during diagnostic thoracentesis and thoracoscopy between July 2012 and July 2019. 55 of the patients had epithelioid mesothelioma.
• Exposure: Not asbestos. Cell lines were treated with cytokines (IL-27, IL-6, a sIL-6R/IL-6 chimeric protein, IFN-γ, and other IL-12 family cytokines). In patients, the levels of IL-27, IL-6, soluble PD-L1 and IFN-γ in pleural fluid were compared with survival. Patients' asbestos exposure was not reported.
• Main results:
  • In the cell lines, IL-27 mainly triggered STAT1 signaling, with weaker STAT3 signaling than the sIL-6R/IL-6 chimeric protein.
  • IL-27 caused an average three-fold increase in surface PD-L1 in the three MM cell lines; IL-6 and the sIL-6R/IL-6 chimera did not change surface PD-L1.
  • IL-27 triggered release of soluble PD-L1 from two of three MM cell lines; IL-6 and the sIL-6R/IL-6 chimera did not.
  • In pleural fluid from the 77 patients, IL-27 levels showed a moderate correlation with soluble PD-L1 levels (R = 0.3781, p = 0.0007).
  • Patients with high IL-27 were more likely than patients with low IL-27 to have high soluble PD-L1 (OR = 4.86, 95% CI 1.86–12.79, p = 0.001). IL-6 level showed no such association (OR = 0.95, 95% CI 0.39–2.32, p = 0.910).
  • Overall survival was counted from the date the pleural effusion was withdrawn to the date of last contact or death from any cause.
  • Over a median follow-up of 42.2 months, 66 of the 77 patients died (printed as 87.0%). Median overall survival was 10.4 months (95% CI 8.0–12.8).
  • Whole cohort: median survival was 13.4 months (95% CI 9.4–17.5) with low soluble PD-L1 versus 7.5 months (95% CI 1.7–13.3) with high soluble PD-L1 (p = 0.011).
  • Whole cohort: median survival was 13.4 months (95% CI 11.3–15.5) with low IL-6 versus 8.6 months (95% CI 6.3–10.9) with high IL-6 (p = 0.001).
  • Whole cohort: IL-27 level did not significantly affect survival (median 10.5 months with low IL-27 versus 9.1 months with high IL-27, p = 0.111).
  • Epithelioid subgroup (n = 55): median survival was 16.6 months (95% CI 0.7–33.5) with low IL-27 versus 9.1 months (95% CI 5.1–13.1) with high IL-27 (p = 0.009).
  • IFN-γ level in pleural fluid did not significantly affect survival (median 10.1 versus 10.4 months, p = 0.858). Patients with high IFN-γ were more likely to have high soluble PD-L1 (OR = 5.16, 95% CI 1.62–16.39, p = 0.005).
• The authors' conclusion: The authors concluded that IL-27 is present at meaningful concentrations in MM pleural fluid and may play an immune regulatory role in advanced-stage MM, possibly by inducing PD-L1 expression.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Mesothelioma, Malignant Mesothelioma, Prognosis, Inflammation, Cytokine, PD-1/PD-L1, Overall Survival.

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