Dataset Information

B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors.

ABSTRACT: The B7 family, and their receptors, the CD28 family, are major immune checkpoints that regulate T-cell activation and function. In the present study, we explore the role of two B7 immune-checkpoints: HERV-H LTR-Associating Protein 2 (HHLA2) and B7 Family Member, H4 (B7x), in the progression of gastrointestinal and pancreatic neuroendocrine tumors (GINETs and PNETs). We demonstrated that both HHLA2 and B7x were expressed to a high degree in human GINETs and PNETs. We determined that the expression of B7x and HHLA2 correlates with higher grade and higher incidence of nodal and distant spread. Furthermore, we confirmed that HIF-1α overexpression is associated with the upregulation of B7x both in our in vivo (animal model) and in vitro (cell culture) models. When grown in vitro, islet tumor β-cells lack B7x expression, unless cultured under hypoxic conditions, which results in both hypoxia-inducible factor 1 subunit alpha (HIF-1α) and B7x upregulation. In vivo, we demonstrated that Men1/B7x double knockout (KO) mice (with loss of B7x expression) exhibited decreased islet β-cell proliferation and tumor transformation accompanied by increased T-cell infiltration compared with Men1 single knockout mice. We have also shown that systemic administration of a B7x mAb to our Men1 KO mice with PNETs promotes an antitumor response mediated by increased T-cell infiltration. These findings suggest that B7x may be a critical mediator of tumor immunity in the tumor microenvironment of NETs. Therefore, targeting B7x offers an attractive strategy for the immunotherapy of patients suffering from NETs.

SUBMITTER: Yuan Z

PROVIDER: S-EPMC8486311 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors.

Yuan Ziqiang Z Gardiner Juliet C JC Maggi Elaine C EC Huang Shuyu S Adem Asha A Bagdasarov Svetlana S Li Guiying G Lee Sylvia S Slegowski Daniel D Exarchakis Alyssa A Howe James R JR Lattime Edmund C EC Zang Xingxing X Libutti Steven K SK

Endocrine-related cancer 20210201 2

The B7 family, and their receptors, the CD28 family, are major immune checkpoints that regulate T-cell activation and function. In the present study, we explore the role of two B7 immune-checkpoints: HERV-H LTR-Associating Protein 2 (HHLA2) and B7 Family Member, H4 (B7x), in the progression of gastrointestinal and pancreatic neuroendocrine tumors (GINETs and PNETs). We demonstrated that both HHLA2 and B7x were expressed to a high degree in human GINETs and PNETs. We determined that the expressio ...[more]

PMID: 33410766

Similar Datasets

Project description:BackgroundNeuroendocrine neoplasms (NENs) comprise a group of rare tumors originating from neuroendocrine cells, which are present in both endocrine glands and scattered throughout the body. Due to their scarcity and absence of specific markers, diagnosing NENs remains a complex challenge. Therefore, new biomarkers are required, ideally, in easy-to-obtain blood samples.MethodsA panel of blood soluble immune checkpoints (sPD-L1, sPD-L2, sPD-1, sCD25, sTIM3, sLAG3, Galectin-9, sCD27, sB7.2 and sSIGLEC5) and cytokines (IL4, IL6, IP10 and MCP1) was quantified in a cohort of 139 NENs, including 29 pituitary NENs, 46 pheochromocytomas and paragangliomas, and 67 gastroenteropancreatic and pulmonary (GEPP) NENs, as well as in 64 healthy volunteers (HVs). The potential of these circulating immunological parameters to distinguish NENs from HVs, differentiate among various NENs subtypes, and predict their prognosis was evaluated using mathematical regression models. These immunological factors-based models generated scores that were evaluated by Receiver Operating Characteristic (ROC) and Area Under the Curve (AUC) analyses. Correlations between these scores and clinical data were performed. From these analyses, a minimal signature emerged, comprising the five shared immunological factors across the models: sCD25, sPD-L2, sTIM3, sLAG3, and Galectin-9. This refined signature was evaluated, validated, and checked for specificity against non-neuroendocrine tumors, demonstrating its potential as a clinically relevant tool for identifying distinct NENs.ResultsMost of the immunological factors analyzed showed specific expression patterns among different NENs. Scores based on signatures of these factors identified NENs with high efficiency, showing AUCs ranging between 0.948 and 0.993 depending on the comparison, and accuracies between 92.52% and 95.74%. These scores illustrated biological features of NENs including the similarity between pheochromocytomas and paragangliomas, the divergence between gastrointestinal and pulmonary NENs, and correlated with clinical features. Furthermore, the models demonstrated strong performance in distinguishing metastatic and exitus GEPP NENs, achieving sensitivities and specificities ranging from 80.95% to 88.89%. Additionally, an easy-to-implement minimal signature successfully identified all analyzed NENs with AUC values exceeding 0.900, and accuracies between 84.11% and 93.12%, which was internally validated by a discovery and validation randomization strategy. These findings highlight the effectiveness of the models and minimal signature in accurately diagnosing and differentiating NENs.ConclusionsThe analysis of soluble immunological factors in blood presents a promising liquid biopsy approach for identifying NENs, delivering critical insights for both prognosis and diagnosis. This study serves as a proof-of-concept for an innovative clinical tool that holds the potential to transform the management of these rare malignancies, providing a non-invasive and effective method for early detection and disease monitoring.

Dataset Information

B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors.

Publications

B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets