Strategies to improve the immunogenicity of anticancer vaccines based on dendritic cell/malignant cell fusions

Abstract

The rationale for fusing dendritic cells (DCs) with whole tumor cells to generate anticancer vaccines resides in the fact that the former operate as potent antigen-presenting cells, whereas the latter express a constellation of tumor-associated antigens (TAAs). Although the administration of DC/malignant cell fusions to cancer patients is safe and this immunotherapeutic intervention triggers efficient tumor-specific T-cell responses in vitro, a limited number of objective clinical responses to DC/cancer cell fusions has been reported thus far. This review discusses novel approaches to improve the immunogenicity of DC/malignant cell fusions as anticancer vaccines.

Keywords: cytotoxic T lymphocyte; dendritic cell; fusion; immunogenicity; whole tumor cell.

Figure 1. Fusions generated with dendritic cells and whole malignant cells. The heterotypic cells obtained by the fusion of dendritic cells (DCs) and whole cancer cells express MHC class I and II molecules, co-stimulatory factors and tumor-associated antigens (TAAs). DC/cancer cell fusions are able to process tumor-associated antigen (TAA)-derived peptides and load them on MHC class I molecules in the endoplasmic reticulum, resulting in the expression on the cell surface of peptide/MHC class I complexes for presentation to CD8⁺ T cells. DC/malignant cell fusions can also process TAA-derived MHC class II-restricted peptides and efficiently present them to CD4⁺ T cells, which are important for the efficient induction of cytotoxic T lymphocyte (CTL) responses.

Figure 2. Generation of immunogenic cancer cells fused to activated dendritic cells. Immunogenic cancer cells expressing calreticulin (CRT) as well as heat-shock proteins (HSPs) on their surface, releasing high-mobility group box 1 (HMGB1) and secreting low levels of immunosuppressive mediators such as transforming growth factor β1 (TGFβ1) can be fused with Toll-like receptor (TLR)-activated dendritic cells (DCs), resulting in the further inhibition of TGFβ1 secretion as well as in the increased released of interleukin-12 (IL-12) and HSPs. These immunogenic DC/cancer cell fusions effectively activate CD4⁺ and CD8⁺ T cells that are capable of producing high levels of interferon γ (IFNγ), eliciting potent antigen-specific cytotoxic T lymphocyte (CTL) responses in vitro.