title: CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor.
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.
authors.affiliation: Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Roncella
authors.affiliation: Department of Internal Medicine (DIMI), University of Genoa, Genoa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Laurent
authors.affiliation: Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fontana
authors.affiliation: Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ferro
authors.affiliation: Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy.
authors.forename: Maria Cristiana
authors.initials: MC
authors.lastname: Franceschini
authors.affiliation: Division of Histopathology and Cytopathology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Salvi
authors.affiliation: Division of Histopathology and Cytopathology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Varesano
authors.affiliation: Division of Histopathology and Cytopathology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Boccardo
authors.affiliation: Unit of Clinical Oncology, ASL5, La Spezia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Vigani
authors.affiliation: Unit of Tumor Epigenetics, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Morabito
authors.affiliation: Division of Pneumology, ASL5, La Spezia, Italy.
authors.forename: Pier Aldo
authors.initials: PA
authors.lastname: Canessa
authors.affiliation: Unit of Radiodiagnostic, ASL5, La Spezia, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Giannoni
authors.affiliation: Unit of Radiodiagnostic, ASL5, La Spezia, Italy.
authors.forename: Ilan
authors.initials: I
authors.lastname: Rosenberg
authors.affiliation: Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Valentino
authors.affiliation: Division of Histopathology and Cytopathology, ASL5, La Spezia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Fedeli
authors.affiliation: Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Domenico Franco
authors.initials: DF
authors.lastname: Merlo
authors.affiliation: Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceppi
authors.affiliation: Blood Transfusion Centre, IRCCS AOU-San Martino-IST, Genoa, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Riggio
authors.affiliation: Unit of Tumor Epigenetics, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Romani
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Saverino
authors.affiliation: Unit of Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: Unit of Tumor Epigenetics, IRCCS AOU San Martino-IST, Genoa, Italy. mariapia.pistillo@hsanmartino.it.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Pistillo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060908:CTLA-4 Antigen / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human
keywords: CTLA-4; Mesothelioma; Overall survival; Pleural effusion; Prognostic factor