PD-L1, PD-l2 and CTLA-4 expression analysis with immunohistochemical and real-time pcr methods in malignant pleural mesothelioma

Malignant mesothelioma is a tumor developing from serous surfaces of pleura, which is a 90% possibility, peritoneum, pericardium and rarely from tunica vaginalis. The most important factors known in the etiology of malignant pleural mesothelioma are contact with asbestos or erionite fibers. Malignant mesothelioma is observed in three basic histological forms: epithelioid, sarcomatoid or mixed (biphasic). The long-term survival rate of malignant mesothelioma patients is poor. This has led to the search for new treatment methods, such as antibodies that block immunocontrol points. Immuno-control points are responsible for controlling the immune system to avoid autoimmunity and prevent tissue damage. CTLA-4 (CD152) is an immunosuppressant receptor mainly found in T-cells and in less active B-cells, monocytes, dendritic cells, and granulocytes. The predominance of co-inhibitory pathways has been shown to affect the ability of the tumor to avoid immunosystem control in cancer. PD-1 (CD279) is a member of the immunoglobulin superfamily. PD-1 from the B7 / CD28 costimulatory receptor family regulates T-cell activation by binding to the programmed death ligand 1 (PD-L1; CD274) and the programmed death ligand 2 (PD-L2; CD273). PD-1 binding inhibits T-cell proliferation, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and IL-2 production and decreases T-cell survival. PD-1 binds to the PD-L1 and PD-L2 inhibitor molecules of the B7 family in particular, thus preventing autoimmunity and avoiding tissue damage. In this study, we aimed to investigate the expression of CTLA-4, PD-L1 and PD-L2 immuno-control receptors in malignant pleural mesothelioma patients and the relationship between this expression and tumor types and prognostic parameters. In our study, 50 patients with malignant pleural mesothelioma were selected from pleural biopsy, decortication and mass excision materials evaluated at Dicle University Faculty of Medicine in the Department of Pathology between 2010 and 2017. 44 cases were epitheloid type, 1 case was sarcomatoid type and 5 of the cases were biphasic type according to the classification by World Health Organization. In all cases, PD-L1, PD-L2 and CTLA-4 were studied by immunohistochemical and vi Real-Time PCR methods. Mean survival times of the patients were determined. Immunohistochemical and RT-PCR study results were compared in terms of age, gender, histological subtype and mean survival times. Kruskal Wallis and Mann Whitney U tests were used for comparative analysis of the groups, and Chi-square test was administered for categorical data. Immunohistochemical studies showed no statistically significant difference between histologic subtype and CTLA-4, PD-L1 and PD-L2 expression. There was no significant difference between the CTLA-4 and PD-L1 immuno-expression and the survival times of the patients as well. There was a statistically significant correlation between mean survival time and immunohistochemical PD-L2 expression (p=0.045). There was no significant relationship between CTLA-4, PD-L1 and PD-L2 expressions and histological subtype and mean survival time in the study conducted with Real Time-PCR method. Immunohistochemical expression of CTLA-4, PD-L1 and PD-L2 was significantly correlated with CTLA-4, PD-L1 and PD-L2 overexpression by Real Time PCR method (p = 0,004, p = 0,001 and p = 0,029). It is reported in the literature that the degree of PD-L1 expressions in patients with malignant pleural mesothelioma is increased in patients with sarcomatoid differentiation and is associated with poor survival. The lack of a significant relationship with survival in our study may be associated with the insufficienct number of patients with sarcomatoid type malignant pleural mesothelioma. A statistically significant relationship was found between the mean survival time and immunohistochemical PD-L2 expression, and the results are similar to the limited number of studies in the literature, indicating that PD-L2 expression may be associated with good prognosis. In the literature, the data revealing the association of CTLA-4 expression with prognostic parameters in malignant pleural mesothelioma is very limited. In our study, there was no significant relationship between CTLA-4 gene expression and histological subtypes of malignant pleural mesothelioma and mean survival.