Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition
Abstract Multiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenviro...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04104-w |
| _version_ | 1818718229278752768 |
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| author | Sara Petillo Cristina Capuano Rosa Molfetta Cinzia Fionda Abdelilah Mekhloufi Chiara Pighi Fabrizio Antonangeli Alessandra Zingoni Alessandra Soriani Maria Teresa Petrucci Ricciarda Galandrini Rossella Paolini Angela Santoni Marco Cippitelli |
| author_facet | Sara Petillo Cristina Capuano Rosa Molfetta Cinzia Fionda Abdelilah Mekhloufi Chiara Pighi Fabrizio Antonangeli Alessandra Zingoni Alessandra Soriani Maria Teresa Petrucci Ricciarda Galandrini Rossella Paolini Angela Santoni Marco Cippitelli |
| author_sort | Sara Petillo |
| collection | DOAJ |
| description | Abstract Multiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition. |
| first_indexed | 2024-12-17T19:47:44Z |
| format | Article |
| id | doaj.art-027a95b214af4c66bd8400071bbc0d06 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-17T19:47:44Z |
| publishDate | 2021-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-027a95b214af4c66bd8400071bbc0d062022-12-21T21:34:50ZengNature Publishing GroupCell Death and Disease2041-48892021-09-0112911310.1038/s41419-021-04104-wImmunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognitionSara Petillo0Cristina Capuano1Rosa Molfetta2Cinzia Fionda3Abdelilah Mekhloufi4Chiara Pighi5Fabrizio Antonangeli6Alessandra Zingoni7Alessandra Soriani8Maria Teresa Petrucci9Ricciarda Galandrini10Rossella Paolini11Angela Santoni12Marco Cippitelli13Department of Molecular Medicine, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeDepartment of Molecular Medicine, Sapienza University of RomeDepartment of Molecular Medicine, Sapienza University of RomeWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory UniversityDepartment of Experimental Medicine, Sapienza University of RomeInstitute of Molecular Biology and Pathology, National Research Council (CNR)Department of Molecular Medicine, Sapienza University of RomeDepartment of Molecular Medicine, Sapienza University of RomeHematology, Department of Clinical and Molecular Medicine, Sapienza University of RomeDepartment of Experimental Medicine, Sapienza University of RomeDepartment of Molecular Medicine, Sapienza University of RomeDepartment of Molecular Medicine, Sapienza University of RomeDepartment of Molecular Medicine, Sapienza University of RomeAbstract Multiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.https://doi.org/10.1038/s41419-021-04104-w |
| spellingShingle | Sara Petillo Cristina Capuano Rosa Molfetta Cinzia Fionda Abdelilah Mekhloufi Chiara Pighi Fabrizio Antonangeli Alessandra Zingoni Alessandra Soriani Maria Teresa Petrucci Ricciarda Galandrini Rossella Paolini Angela Santoni Marco Cippitelli Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition Cell Death and Disease |
| title | Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition |
| title_full | Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition |
| title_fullStr | Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition |
| title_full_unstemmed | Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition |
| title_short | Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition |
| title_sort | immunomodulatory effect of nedd8 activating enzyme inhibition in multiple myeloma upregulation of nkg2d ligands and sensitization to natural killer cell recognition |
| url | https://doi.org/10.1038/s41419-021-04104-w |
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