Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy

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.

Immunotherapy of mesothelioma: the evolving change of a long-standing therapeutic dream

“…Among different available epigenetic drugs, DHA represents a promising enhancer of immunogenicity of PM cells and a potential inducer of increased immune cell recognition of tumor cells. Several preclinical studies demonstrated that epigenetic remodelling of cancer cells by DHA, in particular decitabine and guadecitabine, induced/up-regulated the expression of different immune-related molecules (i.e., HLA class I, cancer testis antigens (CTA), co-stimulatory molecules, interferon stimulated genes) in cancer cells of different histotypes including PM ( 80 – 82 ) resulting in their improved recognition by immune cells ( 83 – 87 ). DHAs were also demonstrated to sensitize PM cells to the modulation of immune response through the upregulation of several genes involved in crosstalk between dendritic cells and NK cells signaling, dendritic cell maturation and acute phase response signalling ( 87 ).…”

“…Several preclinical studies demonstrated that epigenetic remodelling of cancer cells by DHA, in particular decitabine and guadecitabine, induced/up-regulated the expression of different immune-related molecules (i.e., HLA class I, cancer testis antigens (CTA), co-stimulatory molecules, interferon stimulated genes) in cancer cells of different histotypes including PM ( 80 – 82 ) resulting in their improved recognition by immune cells ( 83 – 87 ). DHAs were also demonstrated to sensitize PM cells to the modulation of immune response through the upregulation of several genes involved in crosstalk between dendritic cells and NK cells signaling, dendritic cell maturation and acute phase response signalling ( 87 ). In addition to DHA, also HDACi, valproic acid (VPA) and vorinostat (SAHA), were investigated and demonstrated to synergized with decitabine to kill PM cells and induce tumor antigen expression in the remaining living tumor cells.…”

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

“…Among these, increased expression of immunogenic antigens, induced by the DNA hypomethylating agent (DHA) decitabine, increases the ability for antigen-specific cytotoxic T lymphocytes (CTL) to recognize and kill GBM cells [17]. Along this line, it has been highly demonstrated that epigenetic remodeling of cancer cells of different histotypes by decitabine and guadecitabine induced/up-regulated the expression of different immune molecules (i.e., HLA class I, cancer-testis antigens (CTA), co-stimulatory molecules, interferon-stimulated genes), resulting in improved immune recognition of tumor cells [18][19][20][21][22]. Noteworthy, the potential of DHAs to cross the BBB to reach tumor cells within the brain were confirmed by several in vivo studies [23,24].…”