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Article

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment

1
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, USA
2
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
3
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
4
Abramson Cancer Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
5
Department of Pathology, Orlando VA Medical Center, 13800 Veterans Way, Orlando, FL 32827, USA
6
Department of Medical Education, College of Medicine, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Cinzia Solinas and Pushpamali de Silva
Int. J. Mol. Sci. 2021, 22(24), 13175; https://doi.org/10.3390/ijms222413175
Received: 10 November 2021 / Revised: 25 November 2021 / Accepted: 2 December 2021 / Published: 7 December 2021
(This article belongs to the Special Issue Frontiers in Immuno-Oncology)
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+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ 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. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; polyamine metabolism; tumor microenvironment; immune suppression; MYC; KRAS; c-RAF; DFMO; GW5074 pancreatic ductal adenocarcinoma; polyamine metabolism; tumor microenvironment; immune suppression; MYC; KRAS; c-RAF; DFMO; GW5074
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MDPI and ACS Style

Nakkina, S.P.; Gitto, S.B.; Beardsley, J.M.; Pandey, V.; Rohr, M.W.; Parikh, J.G.; Phanstiel, O., IV; Altomare, D.A. DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment. Int. J. Mol. Sci. 2021, 22, 13175. https://doi.org/10.3390/ijms222413175

AMA Style

Nakkina SP, Gitto SB, Beardsley JM, Pandey V, Rohr MW, Parikh JG, Phanstiel O IV, Altomare DA. DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment. International Journal of Molecular Sciences. 2021; 22(24):13175. https://doi.org/10.3390/ijms222413175

Chicago/Turabian Style

Nakkina, Sai Preethi, Sarah B. Gitto, Jordan M. Beardsley, Veethika Pandey, Michael W. Rohr, Jignesh G. Parikh, Otto Phanstiel IV, and Deborah A. Altomare. 2021. "DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment" International Journal of Molecular Sciences 22, no. 24: 13175. https://doi.org/10.3390/ijms222413175

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