Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-03-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI142137 |
| _version_ | 1818531237326749696 |
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| author | Nabil Hajji Juan Garcia-Revilla Manuel Sarmiento Soto Richard Perryman Jake Symington Chad C. Quarles Deborah R. Healey Yijie Guo Manuel Luis Orta-Vázquez Santiago Mateos-Cordero Khalid Shah John Bomalaski Giulio Anichini Andreas G. Tzakos Timothy Crook Kevin O’Neill Adrienne C. Scheck Jose Luis Venero Nelofer Syed |
| author_facet | Nabil Hajji Juan Garcia-Revilla Manuel Sarmiento Soto Richard Perryman Jake Symington Chad C. Quarles Deborah R. Healey Yijie Guo Manuel Luis Orta-Vázquez Santiago Mateos-Cordero Khalid Shah John Bomalaski Giulio Anichini Andreas G. Tzakos Timothy Crook Kevin O’Neill Adrienne C. Scheck Jose Luis Venero Nelofer Syed |
| author_sort | Nabil Hajji |
| collection | DOAJ |
| description | New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials. |
| first_indexed | 2024-12-11T17:29:50Z |
| format | Article |
| id | doaj.art-7a43ba7a6e2c46269a07eda280cc60bf |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-12-11T17:29:50Z |
| publishDate | 2022-03-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-7a43ba7a6e2c46269a07eda280cc60bf2022-12-22T00:56:52ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-03-011326Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumorsNabil HajjiJuan Garcia-RevillaManuel Sarmiento SotoRichard PerrymanJake SymingtonChad C. QuarlesDeborah R. HealeyYijie GuoManuel Luis Orta-VázquezSantiago Mateos-CorderoKhalid ShahJohn BomalaskiGiulio AnichiniAndreas G. TzakosTimothy CrookKevin O’NeillAdrienne C. ScheckJose Luis VeneroNelofer SyedNew approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.https://doi.org/10.1172/JCI142137OncologyTherapeutics |
| spellingShingle | Nabil Hajji Juan Garcia-Revilla Manuel Sarmiento Soto Richard Perryman Jake Symington Chad C. Quarles Deborah R. Healey Yijie Guo Manuel Luis Orta-Vázquez Santiago Mateos-Cordero Khalid Shah John Bomalaski Giulio Anichini Andreas G. Tzakos Timothy Crook Kevin O’Neill Adrienne C. Scheck Jose Luis Venero Nelofer Syed Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors The Journal of Clinical Investigation Oncology Therapeutics |
| title | Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors |
| title_full | Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors |
| title_fullStr | Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors |
| title_full_unstemmed | Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors |
| title_short | Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors |
| title_sort | arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non arginine auxotrophic glioblastoma tumors |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/JCI142137 |
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