Dendritic cells combined with anti-GITR antibody produce antitumor effects in osteosarcoma

Abstract

Abstract. We attempted to enhance the antitumor effects of tumor lysate-pulsed dendritic cells by eliminating regulatory T cells. The combinatorial effects of dendritic cells and agonist anti-glucocorticoid-induced tumor necrosis factor receptor (anti-GITR) antibodies were investigated with respect to enhancement of the systemic immune response, elimination of regulatory T cells, and inhibition of tumor growth. To determine whether the combination of dendritic cells and anti-GITR antibodies could enhance systemic immune responses and inhibit primary tumor growth in a murine osteosarcoma (LM8) model. We established the following 4 groups of C3H mice (20 mice in total): i), control IgG-treated mice; ii), tumor lysate-pulsed dendritic cell-treated mice; iii), agonist anti-GITR antibody-treated mice; and iv), agonist anti-GITR antibody-and tumor lysate-pulsed dendritic cell-treated mice. The mice that received the agonist anti-GITR antibodies and tumor lysate-pulsed dendritic cells displayed inhibited primary growth, prolonged life time, reduced numbers of regulatory T lymphocytes in the spleen, elevated serum interferon-γ levels, increased number of CD8 + T lymphocytes. The mice that received combined therapy had reduced level of immunosuppressive cytokines in tumor tissue and serum. Combining agonist anti-GITR antibodies with tumor lysate-pulsed dendritic cells enhanced the systemic immune response. These findings provide further support for the continued development of agonist anti-GITR antibodies as an immunotherapeutic strategy for osteosarcoma. We suggest that our proposed immunotherapy could be developed further to improve osteosarcoma treatment.

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).…”

Overexpression of Regulatory T Cell-Related Markers (FOXP3, CTLA-4 and GITR) by Peripheral Blood Mononuclear Cells from Patients with Breast Cancer

“…In addition, the combined programmed Death 1 (PD-1) blockade and GITR stimulation induce a powerful antitumor immunity in a murine ovarian cancer model (Lu et al, 2014). In the murine models, the anti-tumor activity of GIRT has been mainly attributed to the stimulation of CTLs and Th1 cells, induction of M1 macrophages and inhibition of Treg cells (Kawano et al, 2015;Patel et al, 2016). Therefore, it seems that GITR may plays different roles in mice and humans (Nocentini et al, 2012).…”

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

“…Modulation of TIMP3, MMP1, MMP3, MMP11 have been shown to influence in vitro invasiveness of OS cells, and enhance in vivo tumorigenicity (34)(35)(36). OS cell interactions with local stromal cells such as mesenchymal stem cells (37) and endothelial cells (38,39), have been found to be pro-tumorigenic, whereas interactions with natural killer cells (40) or primed dendritic cells (41), were shown to have anti-tumor effects.…”