Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma

Our plain-English summary of Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma, by D. Bensaid, T. Blondy, S. Deshayes, et al (Clinical Epigenetics, 2018).

The study

• Authors: D. Bensaid, T. Blondy, S. Deshayes, V. Dehame, P. Bertrand, M. Grégoire, M. Errami, C. Blanquart
• Journal: Clinical Epigenetics
• Published: 2018;10:79
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really efficient treatments are available for this pathology. Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells. We previously showed that a hypomethylating agent (decitabine) and a histone deacetylase inhibitor (HDACi) (valproic acid (VPA)) combination was immunogenic and led to the induction of an anti-tumor immune response in a mice model of mesothelioma. However, VPA is not very specific, is active at millimolar concentrations and is responsible for side effects in clinic. To improve this approach, we studied four newly synthetized HDACi, two hydroxamates (ODH and NODH) and two benzamides (ODB and NODB), in comparison with VPA and SAHA. We evaluated their toxicity on immune cells and their immunogenicity on MPM cells in combination with decitabine.

Results: All the tested HDACi were toxic for immune cells at high concentrations. Combination with decitabine increased toxicity of HDACi only towards T-cell clone. A decrease in the proportion of regulatory T cells and natural killer cells was observed in particular with VPA and ODH. In MPM cells, all HDACi combinations induced NY-ESO-1 cancer testis antigen (CTA) expression and the recognition of the treated cells by a NY-ESO-1 specific T-CD8 clone. However, for MAGE-A1, MAGE-A3 and XAGE-1b mRNA expression, the results obtained depended on the HDACi used and on the CTA studied. Depending on the MPM cell line studied, molecules alone increased moderately PD-L1 expression. When combined, a higher stimulation of this immune check point inhibitor expression was observed. Decitabine-induced anti-viral response seemed to be inhibited in the presence of HDACi.

Conclusions: This work shows that the combination of decitabine and HDACi could be of interest for MPM immunotherapy. However, this combination induced PD-L1 expression which suggests that an association with anti-PD-L1 therapy should be performed to induce an efficient anti-tumor immune response.

In plain English

This laboratory study used cells grown in dishes, not patients or asbestos exposure. The authors compared four new histone deacetylase inhibitors (HDACi: ODH, NODH, ODB, NODB) with two known ones, VPA and SAHA. Each was given alone or after the drug decitabine. The cells were three human pleural mesothelioma cell lines grown from patients' pleural fluid, plus human lymphocytes and a CD8 T-cell clone. All the HDACi were toxic to immune cells at high concentrations. Decitabine strongly lowered the doses that harmed the T-cell clone. VPA and ODH reduced the proportion of regulatory T cells among lymphocytes by about 95%. In Meso96 mesothelioma cells, every combination significantly raised decitabine-induced NY-ESO-1 antigen mRNA, and an NY-ESO-1-specific T-cell clone recognised the treated cells. Effects on other antigens varied with the drug and the antigen. Combinations also raised mRNA for PD-L1, a molecule that can inhibit T-cell responses; in Meso96 this was significant with VPA, SAHA or NODH. The authors concluded that anti-PD-1/PD-L1 treatment needs to be considered alongside these drugs. They noted it was unclear whether some immune-cell effects reflected toxicity or gene regulation.

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 cells comparing four newly synthesized HDAC inhibitors with VPA and SAHA, alone or combined with decitabine
• Who was studied: Three human pleural mesothelioma cell lines (Meso96, Meso34, Meso45) established from patients' pleural effusions, plus lymphocytes from Nantes Hospital and an NY-ESO-1-specific CD8 T-cell clone; results from three independent experiments
• Exposure: Drug treatments, not asbestos. Mesothelioma cells received decitabine 0.5 μM for 72 h, followed for 48 h by one HDACi: VPA 5 mM, SAHA 2.5 μM, ODB 7.5 μM, NODB 2.5 μM, ODH 2.5 μM or NODH 25 nM.
• Main results:
  • All HDACi were toxic to immune cells. The concentrations killing half the cells were lower for the CD8 T-cell clones than for total lymphocytes. On the T-cell clones, these concentrations were strongly decreased when decitabine was added.
  • In lymphocytes, almost all HDACi reduced the proportion of natural killer (NK) cells. The reduction was strongest with ODH and VPA: more than 50% compared with untreated lymphocytes.
  • VPA and ODH decreased the proportion of regulatory T cells among lymphocytes by approximately 95%. The other compounds reduced the proportion by approximately 85 to 70%.
  • In Meso96 mesothelioma cells, all HDACi significantly increased decitabine-induced NY-ESO-1 mRNA. The NY-ESO-1-specific CD8 T-cell clone recognised the treated cells, as measured by its IFN-γ production. HDACi alone had no effect on cancer testis antigen expression.
  • For the other cancer testis antigens (MAGE-A1, MAGE-A3, XAGE-1b), the HDACi generally increased decitabine-induced expression. The size of the effect differed depending on the antigen and the molecule.
  • In Meso96, decitabine alone did not affect PD-L1 mRNA, but combinations with VPA, SAHA or NODH significantly increased it. In Meso34 and Meso45, all combinations increased PD-L1 expression.
  • Decitabine alone raised RIG-1 and MDA5 mRNA in Meso34 and Meso45 but not in Meso96. Adding HDACi reduced this decitabine-induced rise in Meso34 and Meso45.
• The authors' conclusion: The authors concluded that no single molecule was clearly more appropriate for immunogenicity, although NODH could be of interest. They concluded that an anti-PD-1/PD-L1 strategy needs to be considered with decitabine and HDACi for MPM treatment, to overcome a possible induction of PD-L1.
• Limitations the authors state:
  • The authors stated that it was difficult to tell whether the reductions in regulatory T cells and NK cells reflected toxicity or epigenetic regulation of cell markers. They said a mechanistic study is needed.
  • The authors stated that toxicity to the T-cell clone should be considered in treatment protocols.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Pleural Mesothelioma, Pleura, Asbestos Exposure, Pathology, Mesothelioma, PD-L1.

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