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Journal of Translational Medicine

, 6:51

First Online: 15 September 2008Received: 29 June 2008Accepted: 15 September 2008DOI: 10.1186-1479-5876-6-51

Cite this article as: Koido, S., Homma, S., Hara, E. et al. J Transl Med 2008 6: 51. doi:10.1186-1479-5876-6-51

Abstract

BackgroundHuman hepatocellular carcinoma HCC cells express WT1 and-or carcinoembryonic antigen CEA as potential targets for the induction of antitumor immunity. In this study, generation of cytotoxic T lymphocytes CTL and regulatory T cells Treg by fusions of dendritic cells DCs and HCC cells was examined.

MethodsHCC cells were fused to DCs either from healthy donors or the HCC patient and investigated whether supernatants derived from the HCC cell culture HCCsp influenced on the function of DCs-HCC fusion cells FCs and generation of CTL and Treg.

ResultsFCs coexpressed the HCC cells-derived WT1 and CEA antigens and DCs-derived MHC class II and costimulatory molecules. In addition, FCs were effective in activating CD4 and CD8 T cells able to produce IFN-γ and inducing cytolysis of autologous tumor or semiallogeneic targets by a MHC class I-restricted mechanism. However, HCCsp induced functional impairment of DCs as demonstrated by the down-regulation of MHC class I and II, CD80, CD86, and CD83 molecules. Moreover, the HCCsp-exposed DCs failed to undergo full maturation upon stimulation with the Toll-like receptor 4 agonist penicillin-inactivated Streptococcus pyogenes. Interestingly, fusions of immature DCs generated in the presence of HCCsp and allogeneic HCC cells promoted the generation of CD4 CD25 Foxp3 Treg and inhibited CTL induction in the presence of HCCsp. Importantly, up-regulation of MHC class II, CD80, and CD83 on DCs was observed in the patient with advanced HCC after vaccination with autologous FCs. In addition, the FCs induced WT1- and CEA-specific CTL that were able to produce high levels of IFN-γ.

ConclusionThe current study is one of the first demonstrating the induction of antigen-specific CTL and the generation of Treg by fusions of DCs and HCC cells. The local tumor-related factors may favor the generation of Treg through the inhibition of DCs maturation; however, fusion cell vaccination results in recovery of the DCs function and induction of antigen-specific CTL responses in vitro. The present study may shed new light about the mechanisms responsible for the generation of CTL and Treg by FCs.

Lists of AbbreviationsHCChepatocellular carcinoma

HCCspHCC cell culture supernatants

CEAcarcinoembryonic antigen

DCdendritic cell

TAAtumor-associated antigen

FCfusion cell

DCs-auto-HCCpatient-derived DCs fused with autologous HCC cells

DCs-allo-HCChealthy donor-derived DCs fused with allogeneic HCC cells

CTLcytotoxic T lymphocytes

GM-CSFgranulocyte-macrophage colony-stimulating factor

mAbmonoclonal antibody

ODoptical density

PBMCperipheral blood mononuclear cell

Tregregulatory T cells

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-6-51 contains supplementary material, which is available to authorized users.

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Author: Shigeo Koido - Sadamu Homma - Eiichi Hara - Makoto Mitsunaga - Yoshihisa Namiki - Akitaka Takahara - Eijiro Nagasaki - Hide

Source: https://link.springer.com/







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