Journal article
B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors
Endocrine-related cancer, Vol.28(2), pp.135-149
02/01/2021
DOI: 10.1530/ERC-20-0337
PMCID: PMC8486311
PMID: 33410766
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-1 alpha 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 beta-cells lack B7x expression, unless cultured under hypoxic conditions, which results in both hypoxia-inducible factor 1 subunit alpha (HIF-1 alpha) and B7x upregulation. In vivo, we demonstrated that Men1/B7x double knockout (KO) mice (with loss of B7x expression) exhibited decreased islet beta-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.
Details
- Title: Subtitle
- B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors
- Creators
- Ziqiang Yuan - Rutgers Robert Wood Johnson Med Sch, Div Med Oncol, New Brunswick, NJ USAJuliet C. Gardiner - Rutgers, The State University of New JerseyElaine C. Maggi - Rutgers, The State University of New JerseyShuyu Huang - Albert Einstein College of MedicineAsha Adem - Rutgers, The State University of New JerseySvetlana Bagdasarov - Rutgers, The State University of New JerseyGuiying Li - University of IowaSylvia Lee - Rutgers, The State University of New JerseyDaniel Slegowski - Rutgers, The State University of New JerseyAlyssa Exarchakis - Rutgers, The State University of New JerseyJames R. Howe - Roy J. and Lucille A. Carver College of MedicineEdmund C. Lattime - Rutgers, The State University of New JerseyXingxing Zang - Albert Einstein College of MedicineSteven K. Libutti - Rutgers, The State University of New Jersey
- Resource Type
- Journal article
- Publication Details
- Endocrine-related cancer, Vol.28(2), pp.135-149
- DOI
- 10.1530/ERC-20-0337
- PMID
- 33410766
- PMCID
- PMC8486311
- NLM abbreviation
- Endocr Relat Cancer
- ISSN
- 1351-0088
- eISSN
- 1479-6821
- Publisher
- Bioscientifica Ltd
- Number of pages
- 15
- Grant note
- CINJ Biospecimen Repository Shared Resource PC131008 / Department of Defense; United States Department of Defense R01CA175495 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P50CA174521 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30-CA72720-16 / Rutgers Cancer Institute of New Jersey CCSG
- Language
- English
- Date published
- 02/01/2021
- Academic Unit
- Surgery; Internal Medicine
- Record Identifier
- 9984322823402771
Metrics
27 Record Views