OncologyChemoimmunotherapeutic effect of combined treatment with ex vivo generated antigen-presenting immune cells and conventional antitumor agents in a mouse neuroblastoma model

PurposeCombining antitumor immunotherapy with conventional intensive multimodal therapy may be considered for advanced neuroblastoma. We investigated combination therapy with ex vivo generated immunostimulatory cells and intraperitoneal doxorubicin.MethodsImmunogenic death of neuro-2a neuroblastoma cells was induced by doxorubicin or cisplatin (negative control). Mouse bone marrow cells were cultured with granulocyte-macrophage colony-stimulating factor, followed by addition of doxorubicin-killed neuro-2a cells with or without interleukin-4 and/or CpG-oligodeoxynucleotide to induce immunostimulatory cells. CD8α+ lymphocytes were cocultured with killed neuro-2a cells and immunostimulatory cells, and interferon-γ was measured in the supernatant. Furthermore, female A/J mice were injected with viable neuro-2a cells, followed by immunostimulatory cells and doxorubicin. Then intraabdominal tumor nodules were evaluated.ResultsBone marrow-derived immunostimulatory cells only promoted interferon-γ production by CD8α+ lymphocytes after first being stimulated by doxorubicin-killed neuro-2a cells and interleukin-4, followed by CpG-oligodeoxynucleotide. These cells had a surface antigen expression profile compatible with activated dendritic cells and suppressed tumors in mice intravenously injected with neuro-2a cells. Despite a similar surface antigen profile, the in vivo antitumor effect was stronger after injection of immunostimulatory cells induced by doxorubicin-killed neuro-2a cells compared with cells induced by cisplatin-killed neuro-2a cells. Moreover, interferon-γ production was greater when CD8α+ lymphocytes were cocultured with doxorubicin-killed neuro-2a cells and immunostimulatory cells rather than with cisplatin-killed cells.ConclusionCells with antitumor activity can be induced from bone marrow cells. Combining such cells with doxorubicin may activate antitumor immunity in tumor-bearing mice. Interactions between induced immunostimulatory cells and conventional chemotherapy might be important for antitumor immunity.