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

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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.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
Depositing User: Kevin Petrie
Date Deposited: 18 Aug 2020 18:53
Last Modified: 19 Aug 2020 08:49
URI: http://sure.sunderland.ac.uk/id/eprint/12441
ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

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