Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a severe prognosis, and with a long-standing need for more effective therapeutic approaches. However, treatment with immune checkpoint inhibitors is becoming an increasingly effective strategy for MPM patients. In this scenario, epigenetic modifications may negatively regulate the interplay between immune and malignant cells within the tumor microenvironment, thus contributing to the highly immunosuppressive contexture of MPM that may limit the efficacy of immunotherapy. Aiming to further improve prospectively the clinical efficacy of immunotherapeutic approaches in MPM, we investigated the immunomodulatory potential of different classes of epigenetic drugs (i.e., DNA hypomethylating agent (DHA) guadecitabine, histone deacetylase inhibitors VPA and SAHA, or EZH2 inhibitors EPZ-6438) in epithelioid, biphasic, and sarcomatoid MPM cell lines, by cytofluorimetric and real-time PCR analyses. We also characterized the effects of the DHA, guadecitabine, on the gene expression profiles (GEP) of the investigated MPM cell lines by the nCounter platform. Among investigated drugs, exposure of MPM cells to guadecitabine, either alone or in combination with VPA, SAHA and EPZ-6438 demonstrated to be the main driver of the induction/upregulation of immune molecules functionally crucial in host-tumor interaction (i.e., HLA class I, ICAM-1 and cancer testis antigens) in all three MPM subtypes investigated. Additionally, GEP demonstrated that treatment with guadecitabine led to the activation of genes involved in several immune-related functional classes mainly in the sarcomatoid subtype. Furthermore, among investigated MPM subtypes, DHA-induced CDH1 expression that contributes to restoring the epithelial phenotype was highest in sarcomatoid cells. Altogether, our results contribute to providing the rationale to develop new epigenetically-based immunotherapeutic approaches for MPM patients, potentially tailored to the specific histologic subtypes.
Highlights
Malignant pleural mesothelioma (MPM) is a low-frequency thoracic neoplasm arising from mesothelial cells of the pleural cavity, featuring a high aggressiveness (5-year survival rate of about 5%) [1]
Only a sporadic up-regulation of HLA class I antigens expression was observed in MPM cell lines treated with other investigated epigenetic drugs, and a statistically significant difference was detected in one sarcomatoid cell line treated with valproic acid (VPA) and in two sarcomatoid cell lines treated with EPZ-6438, used alone (Figure 1A, Table S1)
No differences in the percentage of HLA class I antigens positive cells was observed after any treatment, in all investigated MPM cell lines
Summary
Malignant pleural mesothelioma (MPM) is a low-frequency thoracic neoplasm arising from mesothelial cells of the pleural cavity, featuring a high aggressiveness (5-year survival rate of about 5%) [1]. The best outcome has been observed for the epithelioid variant; the sarcomatoid phenotype portends a dismal prognosis; the biphasic subtype shows an intermediate survival, depending on the prevalent component of the tumor [4,5]. This histological differentiation of MPM cells suggests that the epithelial-to-mesenchymal transition (EMT) process, by which epithelial cells lose their polarity and cell contacts, acquire the expression of mesenchymal markers, and manifest a migratory phenotype, represents an event in MPM progression [6,7]. A substantial switch from epithelial markers (E-cadherin) to mesenchymal markers (N-cadherin) through epithelioid to biphasic and sarcomatoid subtypes was demonstrated, suggesting the potential usefulness of these EMT-markers in the diagnosis of mesothelioma [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
