BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo
Low-grade glioma (LGG) is the most common brain tumor affecting pediatric patients (pLGG) and BRAF mutations constitute the most frequent genetic alterations. Within the spectrum of pLGGs, approximately 70%–80% of pediatric patients diagnosed with transforming pleomorphic xanthoastrocytoma (PXA) har...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-06-01
|
| Series: | Molecular Therapy: Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S295032992400050X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850162563615031296 |
|---|---|
| author | Alessandro Canella Matthew Nazzaro Mykyta Artomov Lakshmi Prakruthi Rao Venkata Diana Thomas Justin Lyberger Aleksandr Ukhatov Yao Lulu Xing Katherine Miller Gregory Behbehani Nduka M. Amankulor Claudia Katharina Petritsch Prajwal Rajappa |
| author_facet | Alessandro Canella Matthew Nazzaro Mykyta Artomov Lakshmi Prakruthi Rao Venkata Diana Thomas Justin Lyberger Aleksandr Ukhatov Yao Lulu Xing Katherine Miller Gregory Behbehani Nduka M. Amankulor Claudia Katharina Petritsch Prajwal Rajappa |
| author_sort | Alessandro Canella |
| collection | DOAJ |
| description | Low-grade glioma (LGG) is the most common brain tumor affecting pediatric patients (pLGG) and BRAF mutations constitute the most frequent genetic alterations. Within the spectrum of pLGGs, approximately 70%–80% of pediatric patients diagnosed with transforming pleomorphic xanthoastrocytoma (PXA) harbor the BRAF V600E mutation. However, the impact of glioma BRAF V600E cell regulation of tumor-infiltrating immune cells and their contribution to tumor progression remains unclear. Moreover, the efficacy of BRAF inhibitors in treating pLGGs is limited compared with their impact on BRAF-mutated melanoma. Here we report a novel immunocompetent RCAS-BRAF V600E murine glioma model. Pathological assessment indicates this model seems to be consistent with diffuse gliomas and morphological features of PXA. Our investigations revealed distinct immune cell signatures associated with increased trafficking and activation within the tumor microenvironment (TME). Intriguingly, immune system activation within the TME also generated a pronounced inflammatory response associated with dysfunctional CD8+ T cells, increased presence of immunosuppressive myeloid cells and regulatory T cells. Further, our data suggests tumor-induced inflammatory processes, such as cytokine storm. These findings suggest a complex interplay between tumor progression and the robust inflammatory response within the TME in preclinical BRAF V600E LGGs, which may significantly influence animal survival. |
| format | Article |
| id | doaj-art-f87e862d06ba4cdf9ce8b38527e451cf |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-f87e862d06ba4cdf9ce8b38527e451cf2025-08-20T02:22:32ZengElsevierMolecular Therapy: Oncology2950-32992024-06-0132220080810.1016/j.omton.2024.200808BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivoAlessandro Canella0Matthew Nazzaro1Mykyta Artomov2Lakshmi Prakruthi Rao Venkata3Diana Thomas4Justin Lyberger5Aleksandr Ukhatov6Yao Lulu Xing7Katherine Miller8Gregory Behbehani9Nduka M. Amankulor10Claudia Katharina Petritsch11Prajwal Rajappa12The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USAThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USAThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USAThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USADepartment of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, USADepartment of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USADepartment of Electrical Engineering. Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USAThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USADepartment of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USADepartment of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USADepartment of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA; Corresponding author: Claudia K. Petritsch, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Corresponding author: Prajwal Rajappa, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA.Low-grade glioma (LGG) is the most common brain tumor affecting pediatric patients (pLGG) and BRAF mutations constitute the most frequent genetic alterations. Within the spectrum of pLGGs, approximately 70%–80% of pediatric patients diagnosed with transforming pleomorphic xanthoastrocytoma (PXA) harbor the BRAF V600E mutation. However, the impact of glioma BRAF V600E cell regulation of tumor-infiltrating immune cells and their contribution to tumor progression remains unclear. Moreover, the efficacy of BRAF inhibitors in treating pLGGs is limited compared with their impact on BRAF-mutated melanoma. Here we report a novel immunocompetent RCAS-BRAF V600E murine glioma model. Pathological assessment indicates this model seems to be consistent with diffuse gliomas and morphological features of PXA. Our investigations revealed distinct immune cell signatures associated with increased trafficking and activation within the tumor microenvironment (TME). Intriguingly, immune system activation within the TME also generated a pronounced inflammatory response associated with dysfunctional CD8+ T cells, increased presence of immunosuppressive myeloid cells and regulatory T cells. Further, our data suggests tumor-induced inflammatory processes, such as cytokine storm. These findings suggest a complex interplay between tumor progression and the robust inflammatory response within the TME in preclinical BRAF V600E LGGs, which may significantly influence animal survival.http://www.sciencedirect.com/science/article/pii/S295032992400050XTMEpLGGPXABRAF V600ERCASimmunosuppression |
| spellingShingle | Alessandro Canella Matthew Nazzaro Mykyta Artomov Lakshmi Prakruthi Rao Venkata Diana Thomas Justin Lyberger Aleksandr Ukhatov Yao Lulu Xing Katherine Miller Gregory Behbehani Nduka M. Amankulor Claudia Katharina Petritsch Prajwal Rajappa BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo Molecular Therapy: Oncology TME pLGG PXA BRAF V600E RCAS immunosuppression |
| title | BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo |
| title_full | BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo |
| title_fullStr | BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo |
| title_full_unstemmed | BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo |
| title_short | BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo |
| title_sort | braf v600e in a preclinical model of pleomorphic xanthoastrocytoma analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo |
| topic | TME pLGG PXA BRAF V600E RCAS immunosuppression |
| url | http://www.sciencedirect.com/science/article/pii/S295032992400050X |
| work_keys_str_mv | AT alessandrocanella brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT matthewnazzaro brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT mykytaartomov brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT lakshmiprakruthiraovenkata brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT dianathomas brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT justinlyberger brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT aleksandrukhatov brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT yaoluluxing brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT katherinemiller brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT gregorybehbehani brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT ndukamamankulor brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT claudiakatharinapetritsch brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo AT prajwalrajappa brafv600einapreclinicalmodelofpleomorphicxanthoastrocytomaanalysisofthetumormicroenvironmentandimmunecellinfiltrationdynamicsinvivo |