CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18–0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.
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Pulmonary benign disease
Cytotoxic T lymphocyte antigen-4
Formalin-fixed paraffin embedded
Malignant pleural mesothelioma
Soluble CTLA-4 in PE
Soluble CTLA-4 in serum
Effector T cells
Regulatory T cells
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Supported in part by Grants from the Italian Ministry of Health (5 × 1000 funds 2011), AIL Sezione La Spezia and Fondazione Umberto Veronesi (Grant 2013), Milan, Italy. The authors would like to thank Dr. Roberto Benelli for image analysis and graphical support.
Conflict of interest
The authors declare that they have no conflict of interest.
S. Roncella and S. Laurent contributed equally to this work.
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Roncella, S., Laurent, S., Fontana, V. et al. CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor. Cancer Immunol Immunother 65, 909–917 (2016). https://doi.org/10.1007/s00262-016-1844-3
- Pleural effusion
- Prognostic factor
- Overall survival