In vitro generation of cytotoxic T lymphocyte response using dendritic cell immunotherapy in osteosarcoma

Abstract

Abstract.Immunotherapy with tumor lysate-pulsed dendritic cells (DCs) is one of the breakthrough strategies used in the treatment of cancer. However, DC-based immunotherapies for osteosarcoma are limited. In the present study, preclinical studies of a C3H osteosarcoma mouse model (produced by subcutaneous injection of LM8 murine osteosarcoma cells) validated the concept that LM8 cell lysate-pulsed bone marrow-derived DCs may evoke a more potent immune response compared with DCs that have been matured using polyinosinic:polycytidylic acid (poly I:C). A cytotoxic T lymphocyte (CTL) response was established using two groups of C3H mice (n=9) with osteosarcoma; the treatment group consisted of LM8 cell lysate-pulsed DCs and the control group consisted of DCs matured using poly I:C. Each group was immunized with doses of 1x10 6 cells twice per week for 3 weeks. No difference in the expression of cluster of differentiation markers was identified in the two groups. DCs pulsed with LM8 cell lysate were associated with the increased induction of CTL activity. Serum interferon-γ levels were increased in mice that received DCs pulsed with LM8 cell lysate compared with that in the poly I:C-matured DC group (P<0.041). Serum interleukin-4 was decreased in the treatment group vs. the control group (P<0.033). A mixed lymphocyte reaction assay confirmed that LM8-DC immunotherapy may evoke a significant antigen-specific immune response in a mouse model. The present study reveals promising data on efficacy of a DC-based immunotherapy in the treatment of osteosarcoma; however, further clinical studies are warranted.

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma

“…Masanori Kawano et al [27] reported that combining agonist antiglucocorticoid-induced tumor necrosis factor receptor (GITR) antibodies with tumor lysate-pulsed dendritic cells reduces the amounts of immunosuppressive cytokines in OS tissues as well as serum. Furthermore, it has been confirmed that pulsing of dendritic cells with LM8 cell lysate, derived from OS, efficiently enhances CD4 + and CD8 + T cell proliferation and decreases serum interleukin-4 [28]. While assessing synergistic effects with chemotherapy, it was found that combining doxorubicin, which induces immunogenic cell death, with resting dendritic cells boosts systemic immune reactions, leading to OS inhibition in mouse models [29].…”

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Numerous immunotherapies were assessed to modulate the tumor microenvironment and to reactivate a prolonged and efficient immune response [6]. Adoptive cell therapies based on TIL as described above and generating antigen-specific lymphocytes [103][104][105], dendritic cells [106][107][108][109][110][111][112], NK cells [113][114][115][116][117][118] were developed mostly in vitro and in pre-clinical model of osteosarcoma. Several clinical trials are currently in progress for evaluating their therapeutic efficacy in patients (Table 1).…”

Current and Emerging Targets in Immunotherapy for Osteosarcoma

“…Recently, various kinds of cellular immunotherapy for advanced sarcomas have been developed [38]. Treatment of DCs pulsed with tumor lysate significantly increased induction of cytotoxic T lymphocyte (CTL) activity and increased the serum level IFN- γ [39]. DCs have been used to enhance tumor-specific immune responses because DCs are major antigen-presenting cells initiating cellular immune responses in vivo [40].…”