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CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor

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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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    Authors and Affiliations

    1. Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy

      Silvio Roncella, Paola Ferro, Maria Cristiana Franceschini, Alessandro Valentino & Franco Fedeli

    2. Department of Internal Medicine (DIMI), University of Genoa, Genoa, Italy

      Stefania Laurent

    3. Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy

      Vincenzo Fontana, Domenico Franco Merlo & Marcello Ceppi

    4. Division of Histopathology and Cytopathology, IRCCS AOU San Martino-IST, Genoa, Italy

      Sandra Salvi, Serena Varesano & Simona Boccardo

    5. Unit of Clinical Oncology, ASL5, La Spezia, Italy

      Antonella Vigani

    6. Unit of Tumor Epigenetics, IRCCS AOU San Martino-IST, Genoa, Italy

      Anna Morabito, Massimo Romani & Maria Pia Pistillo

    7. Division of Pneumology, ASL5, La Spezia, Italy

      Pier Aldo Canessa

    8. Unit of Radiodiagnostic, ASL5, La Spezia, Italy

      Ugo Giannoni & Ilan Rosenberg

    9. Blood Transfusion Centre, IRCCS AOU-San Martino-IST, Genoa, Italy

      Salvatore Riggio

    10. Department of Experimental Medicine, University of Genoa, Genoa, Italy

      Daniele Saverino

    11. Unit of Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST, Genoa, Italy

      Alessandro Poggi

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    1. Silvio Roncella
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    Correspondence to Maria Pia Pistillo.

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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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