The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma
Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM’s glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrie...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/22/5550 |
| _version_ | 1797465719537926144 |
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| author | Pravin Kesarwani Shiva Kant Yi Zhao C. Ryan Miller Prakash Chinnaiyan |
| author_facet | Pravin Kesarwani Shiva Kant Yi Zhao C. Ryan Miller Prakash Chinnaiyan |
| author_sort | Pravin Kesarwani |
| collection | DOAJ |
| description | Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM’s glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual functions, we sought to determine if KD influenced the immune landscape of GBM. Consistent with previous publications, KD improved survival in GBM in an immune-competent murine model. Immunophenotyping of tumors identified KD-influenced macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-like-macrophages and a decrease in pro-inflammatory M1-like-macrophages. We recapitulated KD in vitro using a modified cell culture based on metabolomic profiling of serum in KD-fed mice, mechanistically linking the observed changes in macrophage polarization to PPARγ-activation. We hypothesized that parallel increases in M2-macrophage polarization tempered the therapeutic benefit of KD in GBM. To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization. The combination demonstrated a striking improvement in survival and correlative studies confirmed BLZ945 normalized KD-induced changes in macrophage polarization. Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM. |
| first_indexed | 2024-03-09T18:26:33Z |
| format | Article |
| id | doaj.art-8ebfbf4e9aec47708d897602daca68f8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T18:26:33Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8ebfbf4e9aec47708d897602daca68f82023-11-24T07:52:59ZengMDPI AGCancers2072-66942022-11-011422555010.3390/cancers14225550The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in GlioblastomaPravin Kesarwani0Shiva Kant1Yi Zhao2C. Ryan Miller3Prakash Chinnaiyan4Department of Radiation Oncology, Beaumont Health, 3811 West Thirteen Mile Road, Royal Oak, MI 48073, USADepartment of Radiation Oncology, Beaumont Health, 3811 West Thirteen Mile Road, Royal Oak, MI 48073, USADepartment of Radiation Oncology, Beaumont Health, 3811 West Thirteen Mile Road, Royal Oak, MI 48073, USADepartment of Pathology at UAB, Birmingham, AL 35233, USADepartment of Radiation Oncology, Beaumont Health, 3811 West Thirteen Mile Road, Royal Oak, MI 48073, USAGlioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM’s glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual functions, we sought to determine if KD influenced the immune landscape of GBM. Consistent with previous publications, KD improved survival in GBM in an immune-competent murine model. Immunophenotyping of tumors identified KD-influenced macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-like-macrophages and a decrease in pro-inflammatory M1-like-macrophages. We recapitulated KD in vitro using a modified cell culture based on metabolomic profiling of serum in KD-fed mice, mechanistically linking the observed changes in macrophage polarization to PPARγ-activation. We hypothesized that parallel increases in M2-macrophage polarization tempered the therapeutic benefit of KD in GBM. To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization. The combination demonstrated a striking improvement in survival and correlative studies confirmed BLZ945 normalized KD-induced changes in macrophage polarization. Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.https://www.mdpi.com/2072-6694/14/22/5550ketogenic dietGBMimmunosuppressive macrophagesCSF-1R inhibition |
| spellingShingle | Pravin Kesarwani Shiva Kant Yi Zhao C. Ryan Miller Prakash Chinnaiyan The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma Cancers ketogenic diet GBM immunosuppressive macrophages CSF-1R inhibition |
| title | The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma |
| title_full | The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma |
| title_fullStr | The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma |
| title_full_unstemmed | The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma |
| title_short | The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma |
| title_sort | influence of the ketogenic diet on the immune tolerant microenvironment in glioblastoma |
| topic | ketogenic diet GBM immunosuppressive macrophages CSF-1R inhibition |
| url | https://www.mdpi.com/2072-6694/14/22/5550 |
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