title: Dendritic cells combined with doxorubicin induces immunogenic cell death and exhibits antitumor effects for osteosarcoma.
abstract: The effects of dendritic cells (DCs) with low dose doxorubicin on the enhancement of the systemic immune response, including the effects on calreticulin (CRT) expression, heat shock protein 70 (HSP70) on the cell surface expression, and the enhancement of high mobility group box 1 (HMGB1) release from cancer cells, remain unclear. The present study investigated whether the combination of DCs and doxorubicin (ADM) induces immune cell death, and leads to tumor growth inhibition in a murine osteosarcoma model. To evaluate immune response activationin vivo, 4 groups of mice were established: i) untreated mice, ii) DC-treated mice, iii) ADM-treated mice, and iv) DC and ADM-treated mice. Immunological cell death and CRT, HSP70, and HMGB1 expression levels were higher in doxorubicin-treated cells than those in untreated or those treated with DCs alone. NF-κB expression was higher in the DCs after ligand activation using CRT, HSP70, or HMGB1in vitro. Mice treated with DCs and ADM displayed an increased number of CD8+T-lymphocytes within metastatic tumors and inhibition of metastatic growth. The expression of CRT and the release of HMGB1 from tumor tissues were increased in the ADM-treated groups. Treatment with DCs and ADM resulted in the highest serum interferon-γ levels. Combining ADM, which can induce immunogenic cell death, with DCs enhanced the systemic immune response. The findings of the present study provide further support for the continued development of antitumor agents that induce cell death and the immune response to target osteosarcoma.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Itonaga
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsumura
keywords: calreticulin; dendritic cell; doxorubicin; heat shock protein 70; high mobility group box 1; immunogenic cell death; osteosarcoma