Dendritic Cell/Tumor Fusion Vaccine(Beth Israel Deaconess Medical Center)

Dendritic cells (DC) and tumor cell fusion vaccine (DC/tumor cell fusion vaccine) is considered an effective approach in cancer biotherapy. However, its therapeutic effects in early clinical trials have been suboptimal partially due to the immunosuppressive tumor environment. In this study, we used nanoparticles of folate (FA)-modified chitosan, a non-viral vector capable of targeting tumor cells with high expression of FA receptors. FA-chitosan nanoparticles were used as biological carriers for the expression plasmid of the mouse interferon-induced protein-10 (mIP-10) gene, a potent chemoattractant for cytotoxic T cells. The combination of FA-chitosan/mIP-10 and DC/tumor cell fusion vaccine against hepatocellular carcinoma (HCC) effectively inhibited the growth of implanted HCC tumors and prolonged the survival of mice. The combination therapy significantly reduced myeloid-derived suppressor cells (MDSC) in mouse spleen, local tumor, and bone marrow while increasing tumor-specific IFN-γ responses. Furthermore, the combination therapy significantly inhibited tumor cell proliferation while promoting their apoptosis. Taken together, our data illustrate that the mIP-10 enhances the anti-tumor effect of DC/tumor cell fusion vaccine by alleviating the immunosuppressive tumor environment.

Vaccination with fusions of dendritic cells (DCs) and mucin-1 (MUC1)-positive tumor cells (FC/MUC1) induces MUC1-specific antitumor immunity. However, little is known about the function of Cluster of Differentiation (CD)4 T-cells primed with FC/MUC1 in MUC1 transgenic (MUC1.Tg) mice.

CD4 T-cells primed with FC/MUC1 were analyzed by flow cytometry. Antitumor immunity by adoptive transfer of primed CD4 T-cells in Rag2(-/-) mice was assessed.

The effector and memory T-cells generated with FC/MUC1 were crucial to maintenance of long-term antitumor immunity. MUC1-8-mer peptide SAPDTRPA presented by FC/MUC1 was recognized by CD4 and CD8 T-cells. A subset of primed CD4 T-cells possessed cytotoxicity to lyse major histocompatibility complex (MHC) class I and MUC1 positive tumor cells. Interestingly, adoptive transfer of primed CD4 T-cells prevented lung metastasis in Rag2(-/-) mice.

CD4 T-cells primed by FC/MUC1 play direct role in antitumor immunity.