title: TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells.
abstract: Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in neuroblastoma pathogenicity. Recent research in adult cancer patients shows that targeting T-cell check-point molecules PD-1/PD-L1 (or CD279/CD274) may bolster immune reactivity against solid tumors. Also, infections can be associated with spontaneous neuroblastoma regression. In our current study, we therefore investigated if antibody targeting of PD-L1 and triggering of selective pathogen-receptor Toll-like receptors (TLRs) potentiates immunogenicity of neuroblastoma cells. We find this to be the case. TLR3 triggering induced strong upregulation of both MHC class I and PD-L1 on neuroblastoma cells. At the same time TGF-β levels decreased and IL-8 secretion was induced. The combined neuroblastoma cell treatment using PD-L1 blockade and TLR3 triggering using virus analog poly(I:C) moreover induced CD4(+) and CD8(+) T-cell activation. Thus, we propose combined treatment using PD-L1 blockade with synthetic TLR ligands as an avenue toward new immunotherapy against human neuroblastoma.
authors.affiliation: Department of Pediatric Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
authors.affiliation: Department of Pediatric Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Princess Máxima Center for Pediatric Oncology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: f.meyer-wentrup@prinsesmaximacentrum.nl.
authors.forename: Friederike
authors.initials: F
authors.lastname: Meyer-Wentrup
mesh_terms: D000328:Adult; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008213:Lymphocyte Activation; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016209:Interleukin-8; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016212:Transforming Growth Factor beta; D011070:Poly I-C
keywords: Immune checkpoint blockade; Immune therapy; Neuroblastoma; PD-1/PD-L1; TLR ligands in cancer therapy; Therapeutic antibodies