Embryonic Stem Cell–Derived Dendritic Cells Expressing Glypican-3, a Recently Identified Oncofetal Antigen, Induce Protective Immunity against Highly Metastatic Mouse Melanoma, B16-F10

Abstract

We have recently established a method to generate dendritic cells from mouse embryonic stem cells. By introducing exogenous genes into embryonic stem cells and subsequently inducing differentiation to dendritic cells (ES-DC), we can now readily generate transfectant ES-DC expressing the transgenes. A previous study revealed that the transfer of genetically modified ES-DC expressing a model antigen, ovalbumin, protected the recipient mice from a challenge with an ovalbumin-expressing tumor. In the present study, we examined the capacity of ES-DC expressing mouse homologue of human glypican-3, a recently identified oncofetal antigen expressed in human melanoma and hepatocellular carcinoma, to elicit protective immunity against glypican-3-expressing mouse tumors. CTLs specific to multiple glypican-3 epitopes were primed by the in vivo transfer of glypican-3-transfectant ES-DC (ES-DC-GPC3). The transfer of ES-DC-GPC3 protected the recipient mice from subsequent challenge with B16-F10 melanoma, naturally expressing glypican-3, and with glypican-3-transfectant MCA205 sarcoma. The treatment with ES-DC-GPC3 was also highly effective against i.v. injected B16-F10. No harmful side effects, such as autoimmunity, were observed for these treatments. The depletion experiments and immunohistochemical analyses suggest that both CD8 + and CD4 + T cells contributed to the observed antitumor effect. In conclusion, the usefulness of glypican-3 as a target antigen for antimelanoma immunotherapy was thus shown in the mouse model using the ES-DC system. Human dendritic cells expressing glypican-3 would be a promising means for therapy of melanoma and hepatocellular carcinoma. (Cancer Res 2006; 66(4): 2414-22)

Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells

“…This total was estimated to be at least 160 times more than that of the MC-DCs (without c-Myc transduction). Surface phenotype of PSC-derived cells in the stages of MCs and pMCs The myeloid cells (days [13][14] were a heterogeneous population, almost 90% of which was characterized to be CD11b þ ( Fig. 2A) (Fig.…”

“…Previous studies have established methods of generating DCs from PSCs, and demonstrated the utility of PSC-derived DCs in cancer immunotherapy (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). However, generating a large number of DCs from ESCs or iPSCs has required a scaling-up of the initial volume of undifferentiated PSCs.…”

Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells

“…By genetic engineering, we can generate ES-DCs capable of modulating immune response in an antigen-specific manner. Mouse systems have demonstrated the induction of anti-cancer immunity [6][7][8][9][10] and the prevention of autoimmune disease [11,12] by in vivo administration of genetically engineered ES-DCs.…”

Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer

“…We developed a new anti-cancer immunotherapy with GPC3 as a target (44)(45)(46)(47), and the phase I clinical trial of GPC3-derived peptide vaccination for advanced HCC is now on going. Because this new immunotherapy is not indicated for ICC, immunohistochemical staining of GPC3 is a useful method to select eligible patients.…”