Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells

Abstract

Active cancer immunotherapy relies on functional tumor-specific effector T lymphocytes for tumor elimination. Dendritic cells (DCs), as most potent antigen-presenting cells, have been popularly employed in clinical and experimental tumor treatments. We have previously demonstrated that lentiviral vector-mediated transgene delivery to DC progenitors, including bone marrow cells and hematopoietic stem cells, followed by transplantation supports systemic generation of great numbers of tumor antigen-presenting DCs. These DCs subsequently stimulate marked and systemic immune activation. Here, we examined whether this level of immune activation is sufficient to overcome tumor-induced tolerogenic environment for treating an established aggressive epithelial tumor. We showed that a combination treatment of granulocyte macrophage-colony stimulating factor and cytosine-phosphate-guanine-containing oligonucleotide stimulated large numbers of tumor antigen-presenting DCs in situ from transgene-modified stem cells. Moreover, these in situ generated and activated DCs markedly stimulated activation of antigen-specific CD4 and CD8 T cells by augmenting their numbers, as well as function, even in a tumor-bearing tolerogenic environment. This leads to significant improvement in the therapeutic efficacy of established pulmonary metastases. This study suggests that lentiviral vector-modified stem cells as DC progenitors may be used as an effective therapeutic regimen for treating metastatic epithelial tumors. © 2008 Nature Publishing Group All rights reserved.