Abstract
Application of dendritic cells (DCs) pulsed with tumor-associated antigens is considered attractive in immunotherapy for hepatocellular carcinoma (HCC). In order to efficiently prime tumor-associated antigens specific for cytotoxic T lymphocytes (CTLs), it is important that DCs present tumor-associated antigens on MHC class I. MHC class I generally present endogenous antigens expressed in the cytosol. In this study, we developed a new antigen delivery tool based on cross presentation of exogenous antigens in DCs by using cytoplasmic transduction peptide (CTP). CTP protein could transduce FoxM1 tumor antigen into the cytosol of DCs, and CTP-FoxM1 fusion protein could stimulate activation and maturation of DCs. DCs pulsed with CTP-FoxM1 could induce specific CTLs. More importantly, the immunity induced by DCs loaded with CTP-FoxM1 could significantly inhibit tumor growth and metastasis in HCC-bearing mice, which was more potent than that induced by DCs loaded with FoxM1 or CTP, alone. Our results indicate that DCs pulsed with CTP-FoxM1 might be a promising vaccine candidate for HCC therapy and provide new insight into the design of DC-based immunotherapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant diseases worldwide with a poor prognosis and a high mortality rate [1]
In an attempt to confirm whether exogenous CTPFoxM1 fusion protein was localized in cytoplasm, dendritic cells (DCs) were incubated with recombinant Cytoplasmic transduction peptide (CTP)-Forkhead box protein M1 (FoxM1), CTP or FoxM1 proteins
We demonstrated that the majority of the CTP-FoxM1specific fluorescent (FITC) signals were detected in the cytoplasm, and they were clearly separated from the nucleus-specific DAPI signals in the DCs incubated with CTP-FoxM1 (Figure 2)
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant diseases worldwide with a poor prognosis and a high mortality rate [1]. In dendritic cell-based cancer immunotherapy, it is important that DCs should present tumor-associated antigens on MHC class I, which leads to tumor-specific CTL response [7]. It is important to develop an approach capable of directly delivering exogenous antigens as endogenous antigens into the cytosol of DCs in DC-based cancer immunotherapy. Cytoplasmic transduction peptide (CTP) is a newly designed transduction peptide which can carry molecules across the cell membrane and locate them into the cytoplasmic compartment [9, 10, 11] This function of CTP is beneficial for the development of class I-associated CTL vaccines with no side effects on nuclear genetic materials [12, 13]. Our previous study has demonstrated that CTP fusion could transfer bacterial beta-galactosidase into the cytoplasmic compartments in BaF3-BCR/ ABL cells and in mouse models [14], suggesting that exogenous antigens fused to CTP could be recognized as endogenous antigens when delivered into the cytosol, facilitating the use of CTP fusion protein transduction as a promising antigen delivery system in DC-based cancer immunotherapy
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