Abstract
HCC stem cells were reported as posttreatment residual tumor cells that play a pivotal role in tumor relapse. Fusing dendritic cells (DCs) with tumor cells represents an ideal approach to effectively activate the antitumor immunity in vivo. DC/HCC stem cell vaccine provides a potential strategy to generate polyclonal immune response to multiple tumor stem cell antigens including those yet to be unidentified. To assess the potential capacity of DC/HCC stem cell vaccines against HCC, CD90+HepG2 cells were sorted from the HCC cell line HepG2. DC and CD90+HepG2 and DC and HepG2 fused cells were induced by polyethylene glycol (PEG). The influence of fusion cells on proliferation and immunological function transformation of lymphocytes was assessed by FCM and ELISA assay, respectively. The cytotoxicity assay of specific fusion cell-induced CTLs against HepG2 was conducted by CytoTox 96 Non-Radioactive Cytotoxicity Assay kit in vitro. At last, the prevention of HCC formation in vivo was described in a mouse model. The results of FCM analysis showed that the proportion of CD90+HepG2 cells in the spheral CD90+HepG2 enriched by suspension sphere culture was ranging from 98.7% to 99.5%, and 57.1% CD90+HepG2/DC fused cells were successfully constructed. The fusion cells expressed a higher level of costimulatory molecules CD80, CD83, CD86, and MHC-I and MHC-II molecules HLA-ABC and HLA-DR than did immature DCs (P < 0.05). And the functional analysis of fusion cell-induced CTLs also illustrated that CD90+HepG2/DC fusion cells showed a greater capacity to activate proliferation of lymphocytes in vitro (P < 0.05). The CD90+HepG2/DC-activated CTLs had a specific killing ability against CD90+HepG2 cells in vivo. These results suggested that CD90+HepG2/DC fusion cells could efficiently stimulate T lymphocytes to generate specific CTLs targeting CD90+HepG2 cells. It might be a promising strategy of immunotherapy for HCC.
Highlights
HCC is a common malignancy with a dismal prognosis
There is ample evidence that fusion of dendritic cells (DCs) with tumor cells is an effective approach for introducing tumor antigens into DCs
The tumor/DC fusion cell expresses the whole set of tumor antigens in the setting of costimulatory and major histocompatibility (MHC) molecules and facilitates access of tumor antigens to endogenous and exogenous pathways of antigen presentation, resulting in the induction of both CD4 and CD8 T cells
Summary
HCC is a common malignancy with a dismal prognosis. Only a minority of patients are eligible for surgery, and the five-year survival rate of HCC is less than 15% because of metastasis and recurrence [1, 2]. DC/tumor fusion cells, first reported by Gong et al [11], can process and present a broad array of tumor antigens including tumor-associated Ag (TAA) and tumor-specific Ag (TSA) to autologous T cells and induce effectively specific T cell immunity. It is reported by Li et al [9] that DC vaccination using lung CSC antigens induced MHC expression, cytokine production, lymphocyte infiltration, and long-term protection against prostate cancer. We developed a DC/CSC vaccine and assessed the CTL responses to HCC CSCs
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