Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity.
Loading...
Embargo End Date
ICR Authors
Authors
Mussai, F
Egan, S
Hunter, S
Webber, H
Fisher, J
Wheat, R
McConville, C
Sbirkov, Y
Wheeler, K
Bendle, G
Petrie, K
Anderson, J
Chesler, L
De Santo, C
Egan, S
Hunter, S
Webber, H
Fisher, J
Wheat, R
McConville, C
Sbirkov, Y
Wheeler, K
Bendle, G
Petrie, K
Anderson, J
Chesler, L
De Santo, C
Document Type
Journal Article
Date
2015-08-01
Date Accepted
2015-05-09
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.
Citation
Cancer research, 2015, 75 (15), pp. 3043 - 3053
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
Research Team
Paediatric Solid Tumour Biology and Therapeutics