Enhanced antitumoral effect of adenovirus-mediated cytosine deaminase gene therapy by induction of antigen-presenting cells through stem cell factor/granulocyte-macrophage colony-stimulating factor gene transfer.
Suicide gene therapy has been studied intensively for the treatment of cancer. A limited antitumoral effect was obtained by intratumoral injection of adenovirus harboring Escherichia coli cytosine deaminase gene (AdCD) in tumor-bearing mice followed by continuous administration of 5-fluorocytosine (5FC). To address the drawbacks of the limited potential for the induction of antitumoral immunity by CD suicide gene therapy, we hypothesized that antigen-presenting cells (APCs) might contribute to the efficient induction of an antitumoral immune response in tumor-bearing mice undergoing suicide gene therapy. We preinjected the mice with murine stem cell factor (SCF)-encoding adenovirus (AdSCF) and murine granulocyte-macrophage colony-stimulating factor (GM-CSF)-encoding adenovirus (AdGM-CSF); after 7 days, the mice were inoculated with CT26 colon adenocarcinoma. AdCD was injected intratumorally into tumor-bearing mice followed by 5FC administration. The results showed that AdSCF/AdGM-CSF treatment could increase the number, surface molecule expression, and function of APCs efficiently. A more significant growth inhibition of established tumors and a prolongation of the survival period were observed in tumor-bearing mice after AdSCF/AdGM-CSF pretreatment in combination with AdCD/5FC therapy when compared with mice treated with AdSCF or AdGM-CSF in combination with AdCD/5FC, or AdCD/5FC alone (P < .01). Cytotoxic T-lymphocyte activity was induced efficiently after the combined therapy, and mRNA of tumor necrosis factor-alpha, interleukin-4, interferon-gamma, and interleukin-2 was present in the tumor mass after combined therapy, suggesting that a more potent antitumoral response was induced by enhanced APCs. Our results demonstrated that AdSCF/AdGM-CSF pretreatment could activate APCs, and that these APCs could present the tumor antigens released from AdCD/5FC-killed tumor cells and activate the antitumoral response of the host, thus increasing the therapeutic efficiency of suicide gene therapy.
Cao
X
X
Department of Immunology, Second Military Medical University, Shanghai, People's Republic of China. caoxt@public3.sta.net.cn
Huang
X
X
Ju
D W
DW
Zhang
W
W
Hamada
H
H
Wang
J
J
D000256:Adenoviridae / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis; D043525:Cytosine Deaminase; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009700:Nucleoside Deaminases / Q000235:genetics*; D019089:Stem Cell Factor / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016207:Cytokines; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase