Abstract
BackgroundApplication of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo.MethodsHuman DC and CIK were generated from peripheral blood mononuclear cells (PBMCs) taken from consenting liver cancer patients. Flow cytometry was used to determine the phenotypes of DC and CIK, and cell proliferation. The tumor growth and anti-tumor activity of these cells were further evaluated using a nude mouse tumor model.ResultsWe demonstrated that DC and CIK significantly enhanced the apoptosis ratio, depending on DC-CIK cell numbers, by increasing caspase-3 protein expression and reducing proliferating cell nuclear antigen (PCNA) protein expression against LCSC. The in vivo data indicated that DC-CIK exhibited significant LCSC cell-induced tumor growth inhibition in nude mice, which was most significant with LCSC antigen loaded DCs.ConclusionsThe results showed, that DC-CIK cells could inhibit HCC and LCSC growths in vitro and in vivo and the most successful DC triggering of cell cytotoxic activity could be achieved by their LCSC antigen loading.
Highlights
Application of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies
By targeting the markers cluster of differentiation (CD) 90 [2], CD44 [3], CD133 [4] and epithelial cell adhesion molecule (EpCAM) [5], it has proven possible to differentiate between liver cancer stem cells (LCSC) and liver cancer cells
Phenotype characteristics of DC and Cytokine-induced killer (CIK) According to a previous protocol [15], after 3–4 days cultivation, DC cells generated from peripheral blood mononuclear cells (PBMCs) formed different sizes of clones
Summary
Application of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo. The CIK possessing the ability to attack tumor cells expressing CD3/CD56 on the cell surface have antitumor activity against a variety of cancer types, when co-cultured with antigen-loaded DCs. there are several reports about DC and CIK therapies, the mechanism of effective inhibition of LCSC by DC and CIK cells remains unclear. This research established a nude mouse LCSC tumorigenic model and hypothesized that the inhibitory effect of DC-CIK co-culture on LCSC is caused by suppressing proliferating cell nuclear antigen (PCNA) and increasing the caspase-3 pathway. We demonstrated a DC printing relationship between DC-CIK numbers and the degree of LCSC induced tumor suppression
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