Cryoimmunologic Antitumor Effects Enhanced by Dendritic Cells in Osteosarcoma

Abstract

Background We previously reported a limb-salvage technique by treating tumor-bearing bone with liquid nitrogen. We also reported systemic antitumor immunity was enhanced by cryotreatment in a murine osteosarcoma (LM8) model. We therefore combined the cryotreatment of tumor with dendritic cells to promote tumor-specific immune responses. Questions/purposes We determined whether our technique could enhance systemic immune response and inhibit metastatic tumor growth in a murine osteosarcoma model. Materials and Methods To evaluate activation of the immune response, we prepared six groups of C3H mice (80 mice total): (1) excision only, (2) dendritic cells without reimplantation of the cryotreated primary tumor, (3) reimplantation of the cryotreated primary tumor alone, (4) dendritic cells combined with reimplantation of the cryotreated primary tumor, (5) dendritic cells exposed to cryotreated tumor lysates without reimplantation of the cryotreated primary tumor, and (6) dendritic cells exposed to cryotreated tumor lysates with reimplantation of the cryotreated primary tumor. We then compared and verified the activation state of each group's antitumor immunity. Results Mice that received dendritic cells exposed to cryotreated tumor lysates with reimplantation of the cryotreated primary tumor group had high serum interferon c, reduced pulmonary metastases, and increased numbers of CD8(+) T lymphocytes in the metastatic areas. Conclusions Combining tumor cryotreatment with dendritic cells enhanced systemic immune responses and inhibited metastatic tumor growth. Clinical Relevance We suggest immunotherapy could be developed further to improve the treatment of osteosarcoma.

Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma

“…Following cryotreatment, the necrotic tumor lesion remains within the body, and the release of tumor antigens by dying cells has been hypothesized to activate a tumor-specific immune response via antigen presentation by antigen-presenting cells (APCs) such as dendritic cells (DCs) to T cells (7,8). A number of tumor studies combining immunomodulation methods such as the injection of Toll-like receptor agonists with cryotreatment have demonstrated a synergistic effect on tumor rejection, and this was attributed to the enhanced activation of APC function (9,10). We developed a method using cryotreated tumor tissue and DCs to enhance tumor-specific immunoreactions since DCs are the main APCs initiating cell-mediated immune responses in vivo (11,12).…”

TNF-α and Tumor Lysate Promote the Maturation of Dendritic Cells for Immunotherapy for Advanced Malignant Bone and Soft Tissue Tumors

“…In this study, levels of IFN-γ and IL-12 were measured before and after the immunotherapy. The immunological responses are commonly evaluated by IL-12 and IFN-γ because these cytokines reflect the activation of the DCs [14], [32]–[35]. Furthermore, it is reported that the existence of tumors does not influence the levels of the serum IL-12 and IFN-γ [32].…”

“…Joyama reported that DCs inhibit primary tumors and metastatic tumors in an osteosarcoma model using LM8 [13]. Kawano reported that frozen tumor and DCs inhibit metastatic tumors, and increase IFN-γ and the migration of CD8-positive cells to the metastatic site in the osteosarcoma model [14]. These reports suggest that DC-based immunotherapy may be effective in the treatment of sarcoma.…”

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

“…However, there have also been advances in the field of immunotherapy for osteosarcoma that have received less attention (3,4). We developed a method using dendritic cells (DCs) to enhance tumor-specific immunoreactions based on the premise that DCs are the main antigen-presenting cells initiating cell-mediated immune responses in vivo (5). Our current strategy involves eliminating immunosuppressive factors such as regulatory T cells (Tregs) and enhancing cell-mediated immunity.…”