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

Our plain-English summary of Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy, by M.F. Lofiego, S. Cannito, C. Fazio, et al (Epigenomes, 2021).

The study

• Authors: M.F. Lofiego, S. Cannito, C. Fazio, F. Piazzini, O. Cutaia, L. Solmonese, F. Marzani, C. Chiarucci, A.M. Di Giacomo, L. Calabrò, S. Coral, M. Maio, A. Covre, On Behalf Of The EPigenetic Immune-Oncology Consortium Airc Epica Investigators
• Journal: Epigenomes
• Published: 2021;5(4)
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study tested drugs that change how genes are switched on and off (epigenetic drugs) on malignant pleural mesothelioma cells grown in the lab, not on patients. The authors used ten cell lines they had grown from pleural fluid of mesothelioma patients in Siena, Italy, covering the epithelioid, biphasic and sarcomatoid subtypes. Asbestos exposure was not studied. Cells were treated with guadecitabine, VPA, SAHA or EPZ-6438, alone or combined with guadecitabine. In tests on five cell lines, guadecitabine raised HLA class I and ICAM-1, molecules involved in immune recognition of tumor cells, in every line, significantly in 4 of 5. Adding the other drugs did not enhance this. Guadecitabine also switched on the cancer testis antigen NY-ESO-1 in 5 of 5 lines and E-cadherin (CDH1) in the sarcomatoid lines. Across all ten lines it changed the expression of an average of 300.8 of 770 genes tested, with immune-related changes mainly in sarcomatoid lines. The authors noted that the number of cell lines was limited. They concluded that guadecitabine is a promising enhancer of these cells' immunogenicity and that the results laid groundwork for further in vivo studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) experiment on human mesothelioma cell lines
• Who was studied: 10 malignant pleural mesothelioma (MPM) cell lines: epithelioid Meso1 and Meso6, biphasic Meso4, Meso5, Meso7 and Meso13, and sarcomatoid Meso2, Meso3, Meso8 and Meso11. They were established by the authors' group from pleural effusions of MPM patients at the University Hospital of Siena, Italy. Five lines were used for flow cytometry and real-time PCR, and all 10 for gene expression profiling. Dates are not given.
• Exposure: No asbestos exposure was studied. The exposures were epigenetic drugs: the DNA hypomethylating agent guadecitabine (1 µM every 12 hours for 2 days); the histone deacetylase inhibitors VPA (1 mM) and SAHA (1.25 µM); and the EZH2 inhibitor EPZ-6438 (1 µM), given at day 3. Drugs were used alone or combined with guadecitabine, and cells were harvested at day 6.
• Main results:
  • Guadecitabine up-regulated HLA class I antigens in all treated cell lines. The increase was statistically significant (p less than or equal to 0.05) in 4 of 5 lines: two sarcomatoid, one biphasic and one epithelioid.
  • Combining the other epigenetic drugs with guadecitabine did not enhance the HLA class I up-regulation induced by a single treatment.
  • Guadecitabine alone up-regulated ICAM-1 in all treated lines. The increase was significant in 4 of 5: one sarcomatoid, one biphasic and two epithelioid.
  • Guadecitabine and guadecitabine-based combinations induced new expression of the cancer testis antigen NY-ESO-1 in 5 of 5 cell lines.
  • CDH1 (E-cadherin), which was not expressed at baseline in the sarcomatoid lines, was induced in those lines only by guadecitabine or guadecitabine-based combinations.
  • In the 10 cell lines treated with guadecitabine, a mean of 300.8 (range 236 to 375) of 770 investigated genes were differentially expressed compared with untreated cells.
  • Up-regulation of immune-related gene classes was predominant in the sarcomatoid cell lines, with lower effects in the other subtypes.
  • Gene expression changes measured by the two methods (real-time PCR and nCounter) were highly correlated (r = 0.99; p less than 0.001).
• The authors' conclusion: The authors concluded that guadecitabine was the main driver of the immunomodulatory effects observed and represents a promising enhancer of the immunogenicity of MPM cells. They said the studies laid the groundwork for further in vivo studies.
• Limitations the authors state:
  • The number of investigated MPM cell lines was limited.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunotherapy, Pleural Mesothelioma, Prognosis, Standing, checkpoint inhibitors, Tumor Microenvironment, EZH2 Inhibitor.

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