Enhanced Tumor-Specific Long-Term Immunity of Hemaggluttinating Virus of Japan-Mediated Dendritic Cell-Tumor Fused Cell Vaccination by Coadministration with CpG Oligodeoxynucleotides

Abstract

Immunization with dendritic cells (DCs) using various Ag-loading approaches has shown promising results in tumor-specific immunotherapy and immunoprevention. Fused cells (FCs) that are generated from DCs and tumor cells are one of effective cancer vaccines because both known and unknown tumor Ags are presented on the FCs and recognized by T cells. In this study, we attempted to augment antitumor immunity by the combination of DC-tumor FC vaccination with immunostimulatory oligodeoxynucleotides containing CpG motif (CpG ODN). Murine DCs were fused with syngeneic tumor cells ex vivo using inactivated hemagglutinating virus of Japan (Sendai virus). Mice were intradermally (i.d.) immunized with FCs and/or CpG ODN. Coadministration of CpG ODN enhanced the phenotypical maturation of FCs and unfused DCs, and the production of Th1 cytokines, such as IFN-γ and IL-12, leading to the induction of tumor-specific CTLs without falling into T cell anergy. In addition, immunization with FCs + CpG ODN provided significant protection against lethal s.c. tumor challenge and spontaneous lung metastasis compared with that with either FCs or CpG ODN alone. Furthermore, among mice that rejected tumor challenge, the mice immunized with FCs + CpG ODN, but not the mice immunized with FCs or CpG ODN alone, completely rejected tumor rechallenge, indicating that CpG ODN provided long-term maintenance of tumor-specific immunity induced by FCs. Thus, the combination of DC-tumor FCs and CpG ODN is an effective and feasible cancer vaccine to prevent the generation and recurrence of cancers.

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

“…Ag presentation by DCs, in the absence of proper costimulation, induces tolerance (1). In particular, recent studies suggest that TLR-agonist CpG ODNs or conserved pathogen-associated molecular patterns, such as OK-432, start the DC maturation process, which is a critical event in the induction of full effector function in T cells (20,31,32,35,41,57,58). Therefore, we next investigated whether DCs activated by a combination of TLR ligation and up-regulated HSPs enhance the immunogenicity of FCs.…”

Induction of Efficient Antitumor Immunity Using Dendritic Cells Activated by Recombinant Sendai Virus and Its Modulation by Exogenous IFN-β Gene

“…In this study, we demonstrated that DCs treated by SeV secrete several inflammatory cytokines, including IL-1␤, IL-6, and TNF-␣, that are strong activators to DCs in mixture (33); however, no knowledge of how DCs exposed to SeV express these cytokines is available at present. A recent important report indicated that DCs treated with SeV produce multiple proinflammatory cytokines independent of TLRs and their adaptors, including MyD88 (34), unlike LPS, CpG (35), or OK-432 (36), which stimulate DCs through a TLR-dependent mechanism.…”

Inactivated Sendai Virus Particles Eradicate Tumors by Inducing Immune Responses through Blocking Regulatory T Cells

“…Murine dendritic cells derived from bone marrow were generated as described from BALB/c mice (12). Briefly, bone marrow of the tibia and femur was flushed with culture medium and then the effluent was filtered through a 40-mesh sieve.…”

“…In addition, HVJ-E has been applied to an anticancer vaccine strategy (11,12). We previously showed that HVJ-E can incorporate and possibly deliver anticancer drugs (13).…”