High CTLA-4 expression correlates with poor prognosis in thymoma patients

// Giorgio Santoni 1 , Consuelo Amantini 2 , Maria Beatrice Morelli 1, 3 , Daniele Tomassoni 2 , Matteo Santoni 4 , Oliviero Marinelli 1, 2 , Massimo Nabissi 1 , Claudio Cardinali 3 , Vittorio Paolucci 4 , Mariangela Torniai 4 , Silvia Rinaldi 4 , Francesca Morgese 4 , Giovanni Bernardini 3, 5 and Rossana Berardi 4 1 School of Pharmacy, University of Camerino, Camerino, Italy 2 School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy 3 Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy 4 Medical Oncology Unit, Universita Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-Lancisi, Salesi di Ancona, Italy 5 I.N.M. Neuromed, Pozzilli, Isernia (IS), Italy Correspondence to: Giorgio Santoni, email: giorgio.santoni@unicam.it Keywords: cytotoxic T lymphocyte antigen 4 (CTLA-4); thymoma; overall survival (OS); tumor-infiltrating leukocytes (TILs) Received: October 14, 2017     Accepted: February 21, 2018     Published: March 30, 2018 ABSTRACT Thymomas, tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4 or CD152) exerts inhibitory activity on T cells, and since its oncogenic role in the progression of different types of tumors, it has emerged as a potential therapeutic target in cancer patients. In this study, we assessed the expression of CTLA-4 both at mRNA and protein levels in paraffin embedded-tissues from patients with thymomas. Furthermore, we evaluated the relationship between CTLA-4 expression and the clinical-pathologic characteristics and prognosis in patients with thymomas. Sixty-eight patients with median age corresponding to 62 years were included in this analysis. Thymomas were classified accordingly to the WHO and Masaoka-Koga for histochemical analysis and for prognostic significance. A statistical difference was found between CTLA-4 mRNA levels in human normal thymus compared with thymoma specimens. CTLA-4 expression was statistically found to progressively increase in A, B1, B2, AB and it was maximal in B3 thymomas. According to Masaoka-Koga pathological classification, CTLA-4 expression was lower in I, IIA and IIB, and higher in invasive III and IV stages. By confocal microscopy analysis we identified the expression of CTLA-4 both in tumor cells and in CD45 + tumor-infiltrating leukocytes, mainly in B3 and AB thymomas. Finally, CTLA-4 overexpression significantly correlates with reduced overall survival in thymoma patients and in atypical thymoma subgroup, suggesting that it represents a negative prognostic factor.