Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells.
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.
Zhang
X
X
Gene Therapy Program, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Zhao
P
P
Kennedy
C
C
Chen
K
K
Wiegand
J
J
Washington
G
G
Marrero
L
L
Cui
Y
Y
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000556:secondary / Q000628:therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D016219:Immunotherapy, Adoptive; D016086:Lentivirus / Q000235:genetics*; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*