title: Inhibition of neuroblastoma cell growth by TREX1-mutated human lymphocytes.
abstract: T lymphocytes play a major role in counteracting cancer occurrence and development.             Immune therapies against cancer are focused on eliciting a cytotoxic T cell response.             This anticancer activity is related to a variety of mechanisms including the activation             of cytokines and proapoptotic mediators. Interferon α is an established inhibitor             of cancer cell growth. A clinical situation involving the coexistence of high             interferon α levels and lymphocyte activation is the Aicardi-Goutières syndrome,             a progressive encephalopathy arising usually during the first year of life characterized             by intracranial basal ganglia calcifications, leukodystrophy and microcephaly.             Aicardi-Goutières syndrome 1 mutation silences the TREX1 gene, a major endogenous             nuclease. The in vitro study presented herein evaluates the efficacy of the TREX1             mutation in potentiating the anticancer properties of T cells. A TREX1-mutated             lymphocyte cell line was derived from an Aicardi-Goutières syndrome patient and             co-cultured with neuroblastoma cells and vascular endothelial cells in the presence             of interferon α. TREX1-mutated lymphocytes exerted marked inhibitory action on             neuroblastoma cell growth. Cathepsin D was recognized by qPCR as the main mediator             produced by TREX1-mutated lymphocytes involved in the inhibition of neuroblastoma             cell growth. These effects were enhanced in the presence of interferon α. Similar             inhibitory effects in cell growth were exerted by TREX1-mutated lymphocytes towards             vascular endothelial cell angiogenesis as evaluated on Matrigel. The results obtained             provide evidence that mutations of the TREX1 gene increase the capability of T-lymphocytes             to inhibit growth of neoplastic neuronal cells and related angiogenesis.
authors.affiliation: Department of Health Sciences, University of Genoa, I-16132 Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pulliero
authors.forename: B
authors.initials: B
authors.lastname: Marengo
authors.forename: C
authors.initials: C
authors.lastname: Domenicotti
authors.forename: M G
authors.initials: MG
authors.lastname: Longobardi
authors.forename: E
authors.initials: E
authors.lastname: Fazzi
authors.forename: S
authors.initials: S
authors.lastname: Orcesi
authors.forename: M
authors.initials: M
authors.lastname: Bianchi
authors.forename: U
authors.initials: U
authors.lastname: Balottin
authors.forename: A
authors.initials: A
authors.lastname: Izzotti
mesh_terms: D002402:Cathepsin D / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D005090:Exodeoxyribonucleases / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology; D009447:Neuroblastoma / Q000235:genetics* / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; D007371:Interferon-gamma; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D002402:Cathepsin D