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Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration
Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance su...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9746918/ https://www.ncbi.nlm.nih.gov/pubmed/36301668 http://dx.doi.org/10.1172/jci.insight.160130 |
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author | Greenberg, Jacques Limberg, Jessica Verma, Akanksha Kim, David Chen, Xiang Lee, Yeon J. Moore, Maureen D. Ullmann, Timothy M. Thiesmeyer, Jessica W. Loewenstein, Zachary Chen, Kevin J. Egan, Caitlin E. Stefanova, Dessislava Bareja, Rohan Zarnegar, Rasa Finnerty, Brendan M. Scognamiglio, Theresa Du, Yi-Chieh Nancy Elemento, Olivier Fahey, Thomas J. Min, Irene M. |
author_facet | Greenberg, Jacques Limberg, Jessica Verma, Akanksha Kim, David Chen, Xiang Lee, Yeon J. Moore, Maureen D. Ullmann, Timothy M. Thiesmeyer, Jessica W. Loewenstein, Zachary Chen, Kevin J. Egan, Caitlin E. Stefanova, Dessislava Bareja, Rohan Zarnegar, Rasa Finnerty, Brendan M. Scognamiglio, Theresa Du, Yi-Chieh Nancy Elemento, Olivier Fahey, Thomas J. Min, Irene M. |
author_sort | Greenberg, Jacques |
collection | PubMed |
description | Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs. |
format | Online Article Text |
id | pubmed-9746918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-97469182022-12-20 Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration Greenberg, Jacques Limberg, Jessica Verma, Akanksha Kim, David Chen, Xiang Lee, Yeon J. Moore, Maureen D. Ullmann, Timothy M. Thiesmeyer, Jessica W. Loewenstein, Zachary Chen, Kevin J. Egan, Caitlin E. Stefanova, Dessislava Bareja, Rohan Zarnegar, Rasa Finnerty, Brendan M. Scognamiglio, Theresa Du, Yi-Chieh Nancy Elemento, Olivier Fahey, Thomas J. Min, Irene M. JCI Insight Research Article Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs. American Society for Clinical Investigation 2022-12-08 /pmc/articles/PMC9746918/ /pubmed/36301668 http://dx.doi.org/10.1172/jci.insight.160130 Text en © 2022 Greenberg et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Greenberg, Jacques Limberg, Jessica Verma, Akanksha Kim, David Chen, Xiang Lee, Yeon J. Moore, Maureen D. Ullmann, Timothy M. Thiesmeyer, Jessica W. Loewenstein, Zachary Chen, Kevin J. Egan, Caitlin E. Stefanova, Dessislava Bareja, Rohan Zarnegar, Rasa Finnerty, Brendan M. Scognamiglio, Theresa Du, Yi-Chieh Nancy Elemento, Olivier Fahey, Thomas J. Min, Irene M. Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration |
title | Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration |
title_full | Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration |
title_fullStr | Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration |
title_full_unstemmed | Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration |
title_short | Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration |
title_sort | metastatic pancreatic neuroendocrine tumors feature elevated t cell infiltration |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9746918/ https://www.ncbi.nlm.nih.gov/pubmed/36301668 http://dx.doi.org/10.1172/jci.insight.160130 |
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