Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity
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- Francis Mussai
- 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
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- Sharon Egan
- 2School of Veterinary Medicine and Science, University of Nottingham, Nottingham, Sutton Bonnington, United Kingdom.
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- Stuart Hunter
- 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
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- Hannah Webber
- 3Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
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- Jonathan Fisher
- 4Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, University College London, United Kingdom.
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- Rachel Wheat
- 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
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- Carmel McConville
- 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
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- Yordan Sbirkov
- 3Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
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- Kate Wheeler
- 5Department of Paediatric Oncology, Children's Hospital Oxford, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
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- Gavin Bendle
- 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
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- Kevin Petrie
- 3Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
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- John Anderson
- 4Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, University College London, United Kingdom.
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- Louis Chesler
- 3Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
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- Carmela De Santo
- 1School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
説明
<jats:title>Abstract</jats:title> <jats:p>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. Cancer Res; 75(15); 3043–53. ©2015 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 75 (15), 3043-3053, 2015-08-01
American Association for Cancer Research (AACR)