Abstract
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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Abbreviations
- APC:
-
Antigen-presenting cells
- BNG:
-
Pulmonary benign disease
- CI:
-
Confidence intervals
- CTLA-4:
-
Cytotoxic T lymphocyte antigen-4
- FFPE:
-
Formalin-fixed paraffin embedded
- GM:
-
Geometric mean
- HR:
-
Hazard ratio
- IHC:
-
Immunohistochemistry
- IRS:
-
Immunoreactive score
- mCTLA-4:
-
Membrane CTLA-4
- MPM:
-
Malignant pleural mesothelioma
- OS:
-
Overall survival
- PE:
-
Pleural effusion
- PE-sCTLA-4:
-
Soluble CTLA-4 in PE
- sCTLA-4:
-
Soluble CTLA-4
- S-sCTLA-4:
-
Soluble CTLA-4 in serum
- Teffs:
-
Effector T cells
- Tregs:
-
Regulatory T cells
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Acknowledgments
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.
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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
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DOI: https://doi.org/10.1007/s00262-016-1844-3