Nouvelle approche immunothérapeutique afin de traiter le neuroblastome réfractaire chez l’enfant
Despite aggressive treatment by chemotherapy followed by transplantation and treatment with anti-tumor cell disialoganglioside (GD2) monoclonal antibody, IL-2, GM-CSF and retinoic acid, 40% of patients with high-risk neuroblastoma (NB) still undergo disease progression or relapse. Furthermore, tumor-initiating cells (TIC) expressing the CD133 marker are present in NB tumors and are more resistant to chemotherapy. To evaluate a new immunotherapeutic approach, we took advantage of the anti-tumor effect of Natural Killer (NK) cells. We hypothesized that activated NK cells would be a potent therapeutic strategy to eliminate TIC and reduce relapse of NB. We aimed to establish the best strategy to increase the NK cell mediated cytotoxicity against NB. NK cell cytotoxic activity is increased by cytokines, chemokines and activated plasmacytoid dendritic cells (pDC) which produce high amounts of interferon-alpha (IFN-α) upon Toll-like receptor stimulation. We investigated NK-cell lytic properties against NB cell lines following activation by IFN-α or activated pDC. Our results reveal an increased cytolytic activity of NK cells against NB cell lines after stimulation by activated pDC, CD133+ (TIC) as well as anti-GD2 resistant NB cells are sensitive to NK cell mediated cytotoxicity following stimulation by activated pDC. We also examined the cellular mechanisms involved in NK cell-mediated lysis of NB cell lines. The increased cytotoxicity is partially mediated by TRAIL induced apoptosis and as well as by the release of cytolytic granules. In conclusion, we propose a new immunotherapeutic approach that can be used in combination with the anti-GD2 therapy for the treatment of high-risk NB patients.
Cellule Natural Killer TRAIL Neuroblastoma Immunotherapy Natural Killer cell Plasmacytoid dendritic cell Tumor-initiating cell TRAIL Degranulation