DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/24/13175 |
| _version_ | 1797503930462109696 |
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| author | Sai Preethi Nakkina Sarah B. Gitto Jordan M. Beardsley Veethika Pandey Michael W. Rohr Jignesh G. Parikh Otto Phanstiel Deborah A. Altomare |
| author_facet | Sai Preethi Nakkina Sarah B. Gitto Jordan M. Beardsley Veethika Pandey Michael W. Rohr Jignesh G. Parikh Otto Phanstiel Deborah A. Altomare |
| author_sort | Sai Preethi Nakkina |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86<sup>+</sup> cells, CD4<sup>+</sup> and CD8<sup>+</sup> T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3<sup>+</sup> lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression. |
| first_indexed | 2024-03-10T03:57:24Z |
| format | Article |
| id | doaj.art-5c13a8f83cbc40488b381cba25de79fa |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:57:24Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5c13a8f83cbc40488b381cba25de79fa2023-11-23T08:42:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241317510.3390/ijms222413175DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor MicroenvironmentSai Preethi Nakkina0Sarah B. Gitto1Jordan M. Beardsley2Veethika Pandey3Michael W. Rohr4Jignesh G. Parikh5Otto Phanstiel6Deborah A. Altomare7Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USAOvarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USABurnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USAOvarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USABurnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USADepartment of Pathology, Orlando VA Medical Center, 13800 Veterans Way, Orlando, FL 32827, USADepartment of Medical Education, College of Medicine, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826, USABurnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USAPancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86<sup>+</sup> cells, CD4<sup>+</sup> and CD8<sup>+</sup> T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3<sup>+</sup> lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.https://www.mdpi.com/1422-0067/22/24/13175pancreatic ductal adenocarcinomapolyamine metabolismtumor microenvironmentimmune suppressionMYCKRAS |
| spellingShingle | Sai Preethi Nakkina Sarah B. Gitto Jordan M. Beardsley Veethika Pandey Michael W. Rohr Jignesh G. Parikh Otto Phanstiel Deborah A. Altomare DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment International Journal of Molecular Sciences pancreatic ductal adenocarcinoma polyamine metabolism tumor microenvironment immune suppression MYC KRAS |
| title | DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment |
| title_full | DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment |
| title_fullStr | DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment |
| title_full_unstemmed | DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment |
| title_short | DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment |
| title_sort | dfmo improves survival and increases immune cell infiltration in association with myc downregulation in the pancreatic tumor microenvironment |
| topic | pancreatic ductal adenocarcinoma polyamine metabolism tumor microenvironment immune suppression MYC KRAS |
| url | https://www.mdpi.com/1422-0067/22/24/13175 |
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