Genetic modification of a murine fibrosarcoma to produce interleukin 7 stimulates host cell infiltration and tumor immunity.
Retroviral-mediated gene transfer was used to introduce and express the gene for murine interleukin 7 (IL-7) in a fibrosarcoma tumor (FSA). The tumorigenicity of these genetically modified FSA cells was greatly decreased in immunologically intact syngeneic mice but was unaltered in T-cell-deprived mice. IL-7-infected tumors that did grow in intact animals from large size inocula did so slowly and had a high incidence of spontaneous regression. Furthermore, mice that had rejected tumors became specifically immune to challenge with uninfected parental tumor cells. IL-7-infected FSA growing in intact mice were heavily infiltrated with host T-cells that were presumably responsible for slow growth and tumor regression, and tumor cells were in the minority. Fluorescence-activated cell sorter analysis showed that there was a 530% increase in T-cells in IL-7-infected FSA compared with control tumors. CD8+ T-cells were particularly elevated, but CD4+ lymphocytes were also increased in number, as were eosinophils and basophils. The CD4+:CD8+ ratio in IL-7-infected FSA was 1:1.7 in comparison to 1:0.6 in control tumors. Lymphocytes isolated from IL-7-producing tumors had greatly enhanced cytotoxicity towards uninfected, parental FSA cells. Killing of non-cross-reacting fibrosarcoma line was also increased but to a much lesser extent. Injection of recombinant human IL-7 directly into established FSA tumors slowed their growth and, in a significant number of instances, caused complete regression. Mice that had rejected tumor became specifically immune. The dose that was needed for this effect was, however, somewhat large: 20 micrograms twice daily for 10 days. This result contrasts with the efficacy of IL-7 gene infection in stimulating responses to the same tumor. These considerations make IL-7 a good candidate for tumor-directed cytokine gene therapy.
McBride
W H
WH
Department of Radiation Oncology, University of California, Los Angeles School of Medicine 90024.
Thacker
J D
JD
Comora
S
S
Economou
J S
JS
Kelley
D
D
Hogge
D
D
Dubinett
S M
SM
Dougherty
G J
GJ
D000818:Animals; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy; D006084:Graft Rejection; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D009365:Neoplasm Regression, Spontaneous; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection / Q000276:immunology
D015851:Interleukin-7; D012333:RNA, Messenger