TY - JOUR
T1 - Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration
AU - Greenberg, Jacques
AU - Limberg, Jessica
AU - Verma, Akanksha
AU - Kim, David
AU - Chen, Xiang
AU - Lee, Yeon J.
AU - Moore, Maureen D.
AU - Ullmann, Timothy M.
AU - Thiesmeyer, Jessica W.
AU - Loewenstein, Zachary
AU - Chen, Kevin J.
AU - Egan, Caitlin E.
AU - Stefanova, Dessislava
AU - Bareja, Rohan
AU - Zarnegar, Rasa
AU - Finnerty, Brendan M.
AU - Scognamiglio, Theresa
AU - Du, Yi Chieh Nancy
AU - Elemento, Olivier
AU - Fahey, Thomas J.
AU - Min, Irene M.
N1 - Funding Information:
This work was supported in part by Goldhirsh Foundation (TJF) and North American Neuroendocrine Tumor Society Young Investigator Award 190177-01 (IMM). We thank the members of the Genomics Resources Core Facility at Weill Cornell Medicine for their help in RNA-Seq library preparation and data processing. We thank MI3 and flow cytometry core facility at Weill Cornell Medicine for their help in flow cytometry analysis and FACS. We thank the Center for Translational Pathology at Weill Cornell Medicine for their service on IHC analysis.
Publisher Copyright:
© 2022, Greenberg et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/12/8
Y1 - 2022/12/8
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.160130
DO - 10.1172/jci.insight.160130
M3 - Article
C2 - 36301668
AN - SCOPUS:85143536206
VL - 7
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 23
M1 - e160130
ER -