Fenretinide sensitizes multidrug-resistant human neuroblastoma cells to antibody-independent and ch14.18-mediated NK cell cytotoxicity

J Mol Med (Berl). 2013 Apr;91(4):459-72. doi: 10.1007/s00109-012-0958-0. Epub 2012 Sep 30.

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Combining passive immunotherapy with an antibody to the disialoganglioside GD2 (ch14.18/SP2/0) and cytokines with 13-cis-retinoic acid for post-myeloablative maintenance therapy increased survival in high-risk NB, but the overall prognosis for these children is still in need of improvement. Fenretinide (4-HPR) is a synthetic retinoid that has shown clinical activity in recurrent NB and is cytotoxic to a variety of cancer cells, in part via the accumulation of dihydroceramides, which are precursors of GD2. We investigated the effect of 4-HPR on CHO-derived, ch14.18-mediated anti-NB effector functions, complement-dependent cytotoxicity (CDC), and antibody-dependent and antibody-independent cellular cytotoxicity (ADCC and AICC, respectively). Here, we demonstrate for the first time that pretreatment of fenretinide-resistant NB cells with 4-HPR significantly enhanced ch14.18/CHO-mediated CDC and ADCC and AICC by both human natural killer cells and peripheral blood mononuclear cells. Treatment with 4-HPR increased GD2 and death receptor (DR) expression in resistant NB cells and induced an enhanced granzyme B and perforin production by effector cells. Blocking of ganglioside synthesis with a glucosylceramide synthase inhibitor abrogated the increased ADCC response but had no effect on the AICC, indicating that GD2 induced by 4-HPR mediates the sensitization of NB cells for ADCC. We also showed that 4-HPR induced increased GD2 and DR expression in a resistant NB xenograft model that was associated with an increased ADCC and AICC response using explanted tumor target cells from 4-HPR-treated mice. In summary, these findings provide an important baseline for the combination of 4-HPR and passive immunotherapy with ch14.18/CHO in future clinical trials for high-risk NB patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Coculture Techniques
  • Complement System Proteins / immunology
  • Drug Resistance, Neoplasm*
  • Female
  • Fenretinide / pharmacology*
  • Gangliosides / metabolism
  • Humans
  • Killer Cells, Natural / immunology*
  • Mice
  • Neuroblastoma / drug therapy
  • Neuroblastoma / immunology*
  • Neuroblastoma / metabolism
  • Receptors, Death Domain / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Gangliosides
  • Receptors, Death Domain
  • Fenretinide
  • ganglioside, GD2
  • dinutuximab
  • Complement System Proteins