Neuroblastoma Cell Lines Are Refractory to Genotoxic Drug-Mediated Induction of Ligands for NK Cell-Activating Receptors

Irene Veneziani, Elisa Brandetti, Marzia Ognibene, Annalisa Pezzolo, Vito Pistoia, Loredana Cifaldi

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, causes death in almost 15% of children affected by cancer. Treatment of neuroblastoma is based on the combination of chemotherapy with other therapeutic interventions such as surgery, radiotherapy, use of differentiating agents, and immunotherapy. In particular, adoptive NK cell transfer is a new immune-therapeutic approach whose efficacy may be boosted by several anticancer agents able to induce the expression of ligands for NK cell-activating receptors, thus rendering cancer cells more susceptible to NK cell-mediated lysis. Here, we show that chemotherapeutic drugs commonly used for the treatment of NB such as cisplatin, topotecan, irinotecan, and etoposide are unable to induce the expression of activating ligands in a panel of NB cell lines. Consistently, cisplatin-treated NB cell lines were not more susceptible to NK cells than untreated cells. The refractoriness of NB cell lines to these drugs has been partially associated with the abnormal status of genes for ATM, ATR, Chk1, and Chk2, the major transducers of the DNA damage response (DDR), triggered by several anticancer agents and promoting different antitumor mechanisms including the expression of ligands for NK cell-activating receptors. Moreover, both the impaired production of reactive oxygen species (ROS) in some NB cell lines and the transient p53 stabilization in response to our genotoxic drugs under our experimental conditions could contribute to inefficient induction of activating ligands. These data suggest that further investigations, exploiting molecular strategies aimed to potentiate the NK cell-mediated immunotherapy of NB, are warranted.

Original languageEnglish
Pages (from-to)4972410
Number of pages10
JournalJournal of Immunology Research
Volume2018
DOIs
Publication statusPublished - Apr 1 2018

Keywords

  • Antineoplastic Agents/pharmacology
  • Camptothecin/analogs & derivatives
  • Cell Line, Tumor
  • Cisplatin/pharmacology
  • Cytotoxicity, Immunologic
  • DNA Damage/genetics
  • Etoposide/pharmacology
  • Humans
  • Immunotherapy, Adoptive/methods
  • Killer Cells, Natural/drug effects
  • Neuroblastoma/drug therapy
  • Reactive Oxygen Species
  • Topotecan/pharmacology
  • Tumor Suppressor Protein p53/metabolism

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