title: Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors.
abstract: BACKGROUND
  Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are malignant primary brain tumors that occur in young infants. Using current standard therapy, up to 80% of the children still dies from recurrent disease. Cellular immunotherapy might be key to improve overall survival. To achieve efficient killing of tumor cells, however, immunotherapy has to overcome cancer-associated strategies to evade the cytotoxic immune response. Whether CNS-PNETs can evade the immune response remains unknown.
  
  
  METHODS
  We examined by immunohistochemistry the immune response and immune evasion strategies in pediatric CNS-PNETs.
  
  
  RESULTS
  Here, we show that CD4+, CD8+, γδ-T-cells, and Tregs can infiltrate pediatric CNS-PNETs, although the activation status of cytotoxic cells is variable. Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors, respectively.
  
  
  CONCLUSIONS
  We show for the first time that brain tumors express direct granzyme inhibitors (serpins) as a potential mechanism to overcome cellular cytotoxicity, which may have consequences for cellular immunotherapy.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: Vermeulen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van Hecke
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Wim G M
authors.initials: WG
authors.lastname: Spliet
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, 79106, Freiburg, Germany.
authors.forename: José
authors.initials: J
authors.lastname: Villacorta Hidalgo
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, 79106, Freiburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Broekhuizen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
mesh_terms: D000293:Adolescent; D055610:Antigens, CD1d / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology*; D018242:Neuroectodermal Tumors, Primitive / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000276:immunology*; D015843:Serpins / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D055610:Antigens, CD1d; D015395:Histocompatibility Antigens Class I; D009363:Neoplasm Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D053804:Granzymes