Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy
DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune m...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01443/full |
| _version_ | 1818128577515749376 |
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| author | Carolina Fazio Alessia Covre Ornella Cutaia Maria Fortunata Lofiego Patrizia Tunici Carla Chiarucci Sara Cannito Gianluca Giacobini James N. Lowder Roberta Ferraldeschi Pietro Taverna Anna Maria Di Giacomo Sandra Coral Michele Maio |
| author_facet | Carolina Fazio Alessia Covre Ornella Cutaia Maria Fortunata Lofiego Patrizia Tunici Carla Chiarucci Sara Cannito Gianluca Giacobini James N. Lowder Roberta Ferraldeschi Pietro Taverna Anna Maria Di Giacomo Sandra Coral Michele Maio |
| author_sort | Carolina Fazio |
| collection | DOAJ |
| description | DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune molecules that play a crucial role in host-tumor immune interactions. To further investigate the clinical potential of diverse epigenetic compounds when combined with immunotherapeutic strategies, we have now compared the tumor immunomodulatory properties of the first generation DHAs, azacytidine (AZA) and decitabine (DAC) and of the next generation DHA, guadecitabine. To this end, human melanoma and hematological cancer cells were treated in vitro with 1 μM guadecitabine, DAC or AZA and then studied by molecular and flow cytometry analyses for changes in their baseline expression of selected immune molecules involved in different mechanism(s) of immune recognition. Results demonstrated a stronger DNA hypomethylating activity of guadecitabine and DAC, compared to AZA that associated with stronger immunomodulatory activities. Indeed, the mRNA expression of cancer testis antigens, immune-checkpoint blocking molecules, immunostimulatory cytokines, involved in NK and T cell signaling and recruiting, and of genes involved in interferon pathway was higher after guadecitabine and DAC compared to AZA treatment. Moreover, a stronger up-regulation of the constitutive expression of HLA class I antigens and of Intercellular Adhesion Molecule-1 was observed with guadecitabine and DAC compared to AZA. Guadecitabine and DAC seem to represent the optimal combination partners to improve the therapeutic efficacy of immunotherapeutic agents in combination/sequencing clinical studies. |
| first_indexed | 2024-12-11T07:35:28Z |
| format | Article |
| id | doaj.art-19f88e57b7774091b03a9ce88cec240f |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T07:35:28Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-19f88e57b7774091b03a9ce88cec240f2022-12-22T01:15:43ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-12-01910.3389/fphar.2018.01443418878Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer ImmunotherapyCarolina Fazio0Alessia Covre1Ornella Cutaia2Maria Fortunata Lofiego3Patrizia Tunici4Carla Chiarucci5Sara Cannito6Gianluca Giacobini7James N. Lowder8Roberta Ferraldeschi9Pietro Taverna10Anna Maria Di Giacomo11Sandra Coral12Michele Maio13Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyAstex Pharmaceuticals, Inc., Pleasanton, CA, United StatesAstex Therapeutics, Cambridge, United KingdomAstex Pharmaceuticals, Inc., Pleasanton, CA, United StatesDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDepartment of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, ItalyDNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune molecules that play a crucial role in host-tumor immune interactions. To further investigate the clinical potential of diverse epigenetic compounds when combined with immunotherapeutic strategies, we have now compared the tumor immunomodulatory properties of the first generation DHAs, azacytidine (AZA) and decitabine (DAC) and of the next generation DHA, guadecitabine. To this end, human melanoma and hematological cancer cells were treated in vitro with 1 μM guadecitabine, DAC or AZA and then studied by molecular and flow cytometry analyses for changes in their baseline expression of selected immune molecules involved in different mechanism(s) of immune recognition. Results demonstrated a stronger DNA hypomethylating activity of guadecitabine and DAC, compared to AZA that associated with stronger immunomodulatory activities. Indeed, the mRNA expression of cancer testis antigens, immune-checkpoint blocking molecules, immunostimulatory cytokines, involved in NK and T cell signaling and recruiting, and of genes involved in interferon pathway was higher after guadecitabine and DAC compared to AZA treatment. Moreover, a stronger up-regulation of the constitutive expression of HLA class I antigens and of Intercellular Adhesion Molecule-1 was observed with guadecitabine and DAC compared to AZA. Guadecitabine and DAC seem to represent the optimal combination partners to improve the therapeutic efficacy of immunotherapeutic agents in combination/sequencing clinical studies.https://www.frontiersin.org/article/10.3389/fphar.2018.01443/fullDNA hypomethylating agentepigeneticscancerimmune phenotypeimmunotherapy |
| spellingShingle | Carolina Fazio Alessia Covre Ornella Cutaia Maria Fortunata Lofiego Patrizia Tunici Carla Chiarucci Sara Cannito Gianluca Giacobini James N. Lowder Roberta Ferraldeschi Pietro Taverna Anna Maria Di Giacomo Sandra Coral Michele Maio Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy Frontiers in Pharmacology DNA hypomethylating agent epigenetics cancer immune phenotype immunotherapy |
| title | Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy |
| title_full | Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy |
| title_fullStr | Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy |
| title_full_unstemmed | Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy |
| title_short | Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy |
| title_sort | immunomodulatory properties of dna hypomethylating agents selecting the optimal epigenetic partner for cancer immunotherapy |
| topic | DNA hypomethylating agent epigenetics cancer immune phenotype immunotherapy |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01443/full |
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