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Immunotherapy with tumor lysate-loaded dendritic cells (DCs) is one of themost promising strategies to induce antitumor immune responses. However, the antitumoractivity of cytotoxic T cells may be restrained by their expression of the inhibitoryT-cell coreceptor cytotoxic T lymphocyte antigen-4 (CTLA-4). By relieving thisrestraint, CTLA-4-blocking antibodies promote tumor rejection, but the full scopeof their most suitable applications has yet to be fully determined. In the presentstudy, we offer proof of a preclinical concept in a C3H mouse osteosarcoma (LM8)model that CTLA-4 blockade cooperates with cryotreated tumor lysate-pulsed DCsin a primary tumor to prevent the outgrowth of lung metastasis. To evaluate immuneresponse activation, we established the following four groups of C3H mice (60 micein total): i) control immunoglobulin G (IgG)-treated mice; ii) tumor lysate-pulsedDC-treated mice; iii) anti-CTLA-4 antibody-treated mice and iv) tumor lysate-pulsedDC- and anti-CTLA-4 antibody-treated mice. The mice that received the tumor lysate-pulsedDCs and anti-CTLA-4 antibody displayed reduced numbers of regulatory T lymphocytesand increased numbers of CD8+ T lymphocytes inside the metastatic tumor, inhibitionof metastatic growth, a prolonged lifetime, reduced numbers of regulatory T lymphocytesin the spleen and high serum interferon-γ levels. Combining an anti-CTLA-4 antibodywith tumor lysate-pulsed DCs enhanced the systemic immune response. To the bestof our knowledge, these findings document for the first time an effect of thecombination of tumor lysate-pulsed DCs and CTLA-4-blocking antibodies in osteosarcoma.We suggest that cryotreated tumor lysate-pulsed DCs, although insufficient ontheir own, may mediate the rejection of metastatic lesions and prevent recurrenceof the disease when combined with CTLA-4 blockade in osteosarcoma patients inthe clinical setting.

oncology reports

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