title: Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity.
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.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom. Francis.mussai@bch.nhs.uk.
authors.forename: Francis
authors.initials: F
authors.lastname: Mussai
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Nottingham, Sutton Bonnington, United Kingdom.
authors.forename: Sharon
authors.initials: S
authors.lastname: Egan
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hunter
authors.affiliation: Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Webber
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, University College London, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fisher
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wheat
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Carmel
authors.initials: C
authors.lastname: McConville
authors.affiliation: Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Yordan
authors.initials: Y
authors.lastname: Sbirkov
authors.affiliation: Department of Paediatric Oncology, Children's Hospital Oxford, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Wheeler
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Bendle
authors.affiliation: Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, University College London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Paediatric Solid Tumour Biology and Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Carmela
authors.initials: C
authors.lastname: De Santo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001119:Arginase / Q000276:immunology / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D049109:Cell Proliferation; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D005732:Gangliosides; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C019403:ganglioside, GD2; D001120:Arginine; C477631:ARG2 protein, human; D001119:Arginase