Patients’ NK cell stimulation with activated plasmacytoid dendritic cells increases dinutuximab-induced neuroblastoma killing

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2020-09, Vol.69 (9), p.1767-1779
• Main Authors: Belounis, Assila, Ayoub, Marina, Cordeiro, Paulo, Lemieux, William, Teira, Pierre, Haddad, Elie, Herblot, Sabine, Duval, Michel
• Format: Article
• Language: English
• Subjects: Adolescent; Adoptive immunotherapy; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigen Presentation - immunology; Blood cells; Cancer Research; CD16 antigen; CD69 antigen; Cell activation; Cell surface; Child; Child, Preschool; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Dendritic cells; Dendritic Cells - immunology; Female; Humans; Immunology; Immunotherapy; Immunotherapy - methods; Immunotherapy, Adoptive - methods; Killer Cells, Natural - immunology; Lymphocyte Activation - immunology; Male; Medicine; Medicine & Public Health; Monoclonal antibodies; Natural killer cells; Neoplasm Recurrence, Local - immunology; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - immunology; Oncology; Original; Original Article; Patients; Targeted cancer therapy; TLR9 protein; Toll-like receptors; Toll-Like Receptors - immunology; TRAIL protein; Tumor cells; α-Interferon
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02581-0

Targeted immunotherapy has improved the outcome of patients with high-risk neuroblastoma (NB). However, immune escape of tumor cells still occurs and about 40% of NB patients relapse and die from their disease. We previously showed that natural killer (NK) cell stimulation by Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC) increases the efficacy of dinutuximab-based immunotherapy against NB cell lines via the TRAIL death-receptor pathway. With the aim to translate our findings into a novel adoptive therapy of TLR-activated pDC, we investigated the pDC/NK cell axis in NB patients undergoing dinutuximab-based immunotherapy. We show that pDC counts were low at the beginning of immunotherapy but reached normal levels over time. Blood NK cell counts were normal in all patients, although a high proportion of CD56 bright CD16 low/− cells was observed. The stimulation of patient’s blood cells with a TLR9 ligand led to IFN-α production by pDC, and TRAIL expression on NK cell surface. Patient’s NK cells expressed high levels of CD69 and TRAIL after stimulation with activated pDC. Both CD56 bright CD16 low/− and CD56 dim CD16 + NK cells degranulated against autologous target cells in the presence of dinutuximab. Importantly, pDC-induced NK cell activation increased the dinutuximab mediated autologous killing of patient-derived NB cells. Altogether, our study demonstrates that TLR-activated pDC strongly increase the cytotoxic functions of NK cells in high-risk NB patients undergoing immunotherapy. These results, therefore, support pDC adoptive immunotherapy as a novel approach to decrease the risk of relapse in patients with high-risk NB.