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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-12-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.160130 |
| _version_ | 1827768028193882112 |
|---|---|
| author | Jacques Greenberg Jessica Limberg Akanksha Verma David Kim Xiang Chen Yeon J. Lee Maureen D. Moore Timothy M. Ullmann Jessica W. Thiesmeyer Zachary Loewenstein Kevin J. Chen Caitlin E. Egan Dessislava Stefanova Rohan Bareja Rasa Zarnegar Brendan M. Finnerty Theresa Scognamiglio Yi-Chieh Nancy Du Olivier Elemento Thomas J. Fahey III Irene M. Min |
| author_facet | Jacques Greenberg Jessica Limberg Akanksha Verma David Kim Xiang Chen Yeon J. Lee Maureen D. Moore Timothy M. Ullmann Jessica W. Thiesmeyer Zachary Loewenstein Kevin J. Chen Caitlin E. Egan Dessislava Stefanova Rohan Bareja Rasa Zarnegar Brendan M. Finnerty Theresa Scognamiglio Yi-Chieh Nancy Du Olivier Elemento Thomas J. Fahey III Irene M. Min |
| author_sort | Jacques Greenberg |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T12:06:40Z |
| format | Article |
| id | doaj.art-6f96a988d4f44b32a06c2793e68c3f00 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:40Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-6f96a988d4f44b32a06c2793e68c3f002023-11-07T16:24:55ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-12-01723Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltrationJacques GreenbergJessica LimbergAkanksha VermaDavid KimXiang ChenYeon J. LeeMaureen D. MooreTimothy M. UllmannJessica W. ThiesmeyerZachary LoewensteinKevin J. ChenCaitlin E. EganDessislava StefanovaRohan BarejaRasa ZarnegarBrendan M. FinnertyTheresa ScognamiglioYi-Chieh Nancy DuOlivier ElementoThomas J. Fahey IIIIrene M. MinPancreatic 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.https://doi.org/10.1172/jci.insight.160130ImmunologyTherapeutics |
| spellingShingle | Jacques Greenberg Jessica Limberg Akanksha Verma David Kim Xiang Chen Yeon J. Lee Maureen D. Moore Timothy M. Ullmann Jessica W. Thiesmeyer Zachary Loewenstein Kevin J. Chen Caitlin E. Egan Dessislava Stefanova Rohan Bareja Rasa Zarnegar Brendan M. Finnerty Theresa Scognamiglio Yi-Chieh Nancy Du Olivier Elemento Thomas J. Fahey III Irene M. Min Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration JCI Insight Immunology Therapeutics |
| 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 | Immunology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.160130 |
| work_keys_str_mv | AT jacquesgreenberg metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT jessicalimberg metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT akankshaverma metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT davidkim metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT xiangchen metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT yeonjlee metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT maureendmoore metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT timothymullmann metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT jessicawthiesmeyer metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT zacharyloewenstein metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT kevinjchen metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT caitlineegan metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT dessislavastefanova metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT rohanbareja metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT rasazarnegar metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT brendanmfinnerty metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT theresascognamiglio metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT yichiehnancydu metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT olivierelemento metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT thomasjfaheyiii metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration AT irenemmin metastaticpancreaticneuroendocrinetumorsfeatureelevatedtcellinfiltration |