title: Expression of NTRK1/TrkA affects immunogenicity of neuroblastoma cells.
abstract: High levels of the NTRK1/TrkA receptor are expressed in low-stage neuroblastomas, which are characterized by a good patient prognosis and often undergo spontaneous regression. In addition to apoptosis, tumor-immune responses might contribute to this regression. We hypothesized that TrkA expression might enhance the immune response to neuroblastomas. Immunohistochemistry on neuroblastoma tissue microarrays confirmed significantly higher lymphocyte infiltration in low-stage compared with high-stage tumors. Flow cytometry of human SH-SY5Y cells stably transfected with NTRK1/TrkA cDNA revealed significant upregulation of major histocompatibility complex (MHC) class I complexes on TrkA-expressing cells. Corresponding to this upregulation, T cell activity and cytoxicity was enhanced in the presence of SY5Y-TrkA cells or by medium conditioned by them, suggesting the existence of additional soluble factors stimulating the T cell response. Activation of natural killer (NK) cells was only increased in the presence of SY5Y-TrkA conditioned medium (CM) and not in co-culture assays, suggesting a dominant inhibitory effect of upregulated MHC class I as the primary NK cell escape mechanism of TrkA-expressing neuroblastomas. We reanalyzed gene expression data obtained from the cell culture model to identify additional genes involved in the TrkA-mediated modulation of immune responses. Upregulation of selected target genes in SY5Y-TrkA cells was confirmed on transcript and protein levels. However, none of the proteins were detected in medium conditioned by SY5Y-TrkA cells, arguing against these factors as soluble mediators of the TrkA-induced immune response. We here provide evidence that TrkA expression in neuroblastoma leads to an increased immunogenicity that may contribute to a less malignant phenotype and/or spontaneous regression of neuroblastoma cells.
authors: Department of Pediatric Oncology and Hematology, University Hospital Essen, Germany. kristian.pajtler@uk-essen.de
authors: Kristian W
authors: KW
authors: Pajtler
authors: Vera
authors: V
authors: Rebmann
authors: Monika
authors: M
authors: Lindemann
authors: Johannes H
authors: JH
authors: Schulte
authors: Stefanie
authors: S
authors: Schulte
authors: Michael
authors: M
authors: Stauder
authors: Ivo
authors: I
authors: Leuschner
authors: Kurt-Werner
authors: KW
authors: Schmid
authors: Ulrike
authors: U
authors: Köhl
authors: Alexander
authors: A
authors: Schramm
authors: Angelika
authors: A
authors: Eggert
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020917:Receptor, trkA / Q000276:immunology*; D046888:Tissue Array Analysis
chemical_list: D017077:Culture Media, Conditioned; D015395:Histocompatibility Antigens Class I; D020917:Receptor, trkA