Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment
Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angio...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-10-01
|
| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI167994 |
| _version_ | 1797634472271675392 |
|---|---|
| author | Eunhyeong Lee Sophie O’Keefe Alessandra Leong Ha-Ram Park Janani Varadarajan Subrata Chowdhury Shannon Hiner Sungsoo Kim Anahita Shiva Richard A. Friedman Helen Remotti Tito Fojo Hee Won Yang Gavin Thurston Minah Kim |
| author_facet | Eunhyeong Lee Sophie O’Keefe Alessandra Leong Ha-Ram Park Janani Varadarajan Subrata Chowdhury Shannon Hiner Sungsoo Kim Anahita Shiva Richard A. Friedman Helen Remotti Tito Fojo Hee Won Yang Gavin Thurston Minah Kim |
| author_sort | Eunhyeong Lee |
| collection | DOAJ |
| description | Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs. |
| first_indexed | 2024-03-11T12:08:17Z |
| format | Article |
| id | doaj.art-eaf9a3bca30a429d8677f001514daa1e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:17Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-eaf9a3bca30a429d8677f001514daa1e2023-11-07T16:20:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-10-0113320Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitmentEunhyeong LeeSophie O’KeefeAlessandra LeongHa-Ram ParkJanani VaradarajanSubrata ChowdhuryShannon HinerSungsoo KimAnahita ShivaRichard A. FriedmanHelen RemottiTito FojoHee Won YangGavin ThurstonMinah KimImproving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.https://doi.org/10.1172/JCI167994Angiogenesis |
| spellingShingle | Eunhyeong Lee Sophie O’Keefe Alessandra Leong Ha-Ram Park Janani Varadarajan Subrata Chowdhury Shannon Hiner Sungsoo Kim Anahita Shiva Richard A. Friedman Helen Remotti Tito Fojo Hee Won Yang Gavin Thurston Minah Kim Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment The Journal of Clinical Investigation Angiogenesis |
| title | Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment |
| title_full | Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment |
| title_fullStr | Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment |
| title_full_unstemmed | Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment |
| title_short | Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment |
| title_sort | angiopoietin 2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting t cell recruitment |
| topic | Angiogenesis |
| url | https://doi.org/10.1172/JCI167994 |
| work_keys_str_mv | AT eunhyeonglee angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT sophieokeefe angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT alessandraleong angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT harampark angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT jananivaradarajan angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT subratachowdhury angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT shannonhiner angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT sungsookim angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT anahitashiva angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT richardafriedman angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT helenremotti angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT titofojo angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT heewonyang angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT gavinthurston angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment AT minahkim angiopoietin2blockadesuppressesgrowthoflivermetastasesfrompancreaticneuroendocrinetumorsbypromotingtcellrecruitment |