Engineered fusion hybrid vaccine of IL-4 gene-modified myeloma and relative mature dendritic cells enhances antitumor immunity

Abstract 

Dendritic cell (DC)-tumor fusion hybrid vaccine which facilitates antigen presentation represents a new powerful strategy in cancer therapy. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between wild-type J558 or engineered J558-IL-4 myeloma cells secreting cytokine interleukin-4 (IL-4) and immature DCs (DC_IMAT) or relative mature DCs (DC_RMAT). DC_RMAT displayed an up-regulated expression of immune molecules (Ia^d, CD40, CD54, CD80 and CD86) and certain cytokines/chemokines, and enhanced ability of allogeneic T cell stimulation when compared to DC_IMAT. These DCs were fused with myeloma cells by polyethylene glycol (PEG). The fusion efficiency was approximately 20%. Our data showed that immunization of C57BL/6 mice with DC_RMAT/J558 hybrids induced protective immunity against a high dose of J558 tumor challenge (1×10⁶ cells) in 3 out of 10 immunized mice, compared with no protection seen in mice immunized with DC_IMAT/J558 hybrids. Furthermore, immunization of mice with engineered DC_RMAT/J558-IL-4 hybrids elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro and induced more efficient protective immunity (10/10 mice; tumor free) against J558 tumor challenge in vivo than DC_RMAT/J558 hybrid vaccines. The results demonstrate the importance of DC maturation in DC-tumor hybrid vaccines and indicate that the engineered fusion hybrid vaccines which combine gene-modified tumor and DC vaccines may be an attractive strategy for cancer immunotherapy.

Abbreviations: APC, antigen presenting cell, BM, bone marrow, cpm, counts per minute, CTL, cytotoxic T lymphocyte, DC, dendritic cell, DMEM, Dulbecco’s modified medium, FCS, fetal calf serum, FITC, fluorescein isothiocyanate, GM-CSF, granulocyte macrophage colony-stimulation factor, ICAM, intercellular adhesion molecule, IL-4, interleukin-4, MIP, macrophage inflammatory protein, MHC, major histocompatibility complex, MLR, mixed lymphocyte reaction, PEG, polyethylene glycol, TRITC, tetramethyl rhodamine, TNF, tumor necrosis factor

Keywords: Dendritic cells, Engineered tumor cells, IL-4, Cell fusion, Antitumor immunity