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Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity.

Mussai, Francis, Egan, Sharon, Hunter, Stuart, Webber, Hannah, Fisher, Jonathan, Wheat, Rachel, McConville, Carmel, Sbirkov, Yordan, Wheeler, Kate, Bendle, Gavin, Petrie, Kevin, Anderson, John, Chesler, Louis and De Santo, Carmela (2015) Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity. Cancer research, 75 (15). pp. 3043-53. ISSN 1538-7445

Item Type: Article

Abstract

Neuroblastoma is the most common extracranial solid tumor of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumor cells suppress T-cell proliferation through increased arginase activity. Arginase II is the predominant isoform expressed and creates an arginine-deplete local and systemic microenvironment. Neuroblastoma arginase activity results in inhibition of myeloid cell activation and suppression of bone marrow CD34(+) progenitor proliferation. Finally, we demonstrate that the arginase activity of neuroblastoma impairs NY-ESO-1-specific T-cell receptor and GD2-specific chimeric antigen receptor-engineered T-cell proliferation and cytotoxicity. High arginase II expression correlates with poor survival for patients with neuroblastoma. The results support the hypothesis that neuroblastoma creates an arginase-dependent immunosuppressive microenvironment in both the tumor and blood that leads to impaired immunosurveillance and suboptimal efficacy of immunotherapeutic approaches.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 12441
Identification Number: https://doi.org/10.1158/0008-5472.CAN-14-3443
ISSN: 1538-7445
URI: http://sure.sunderland.ac.uk/id/eprint/12441
Official URL: https://cancerres.aacrjournals.org/content/75/15/3...

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 18 Aug 2020 18:53
Last Modified: 30 Sep 2020 10:48

Contributors

Author: Kevin Petrie ORCID iD
Author: Francis Mussai
Author: Sharon Egan
Author: Stuart Hunter
Author: Hannah Webber
Author: Jonathan Fisher
Author: Rachel Wheat
Author: Carmel McConville
Author: Yordan Sbirkov
Author: Kate Wheeler
Author: Gavin Bendle
Author: John Anderson
Author: Louis Chesler
Author: Carmela De Santo

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

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