IFN-alpha 1 gene expression into a metastatic murine adenocarcinoma (TS/A) results in CD8+ T cell-mediated tumor rejection and development of antitumor immunity. Comparative studies with IFN-gamma-producing TS/A cells.
Cells from a spontaneous, invasive, and metastasizing mouse mammary adenocarcinoma (TS/A-pc) were transfected with a retroviral vector containing the mouse IFN-alpha 1 gene. TS/A clones secreting varying amounts of IFN-alpha 1 were isolated and their tumorigenicity was evaluated after s.c. or i.v. injection into immunocompetent BALB/c mice. Almost all of the IFN-alpha-secreting TS/A clones failed to grow in a high percentage of mice or formed small tumors after a long latency time, whereas TS/A-pc or transfection control cells always grew into large s.c. tumors. Rejection was mainly mediated by CD8+ T lymphocytes and partially by polymorphonuclear cells, as demonstrated by selective immunosuppression experiments and histologic and ultrastructural data. After rejection, a significant portion of mice displayed an immune resistance to the subsequent challenge with TS/A-pc. When the metastatic ability of IFN-alpha-secreting clones was compared with that of previously characterized IFN-gamma-secreting TS/A clones, it was found that the expression of IFN-alpha into TS/A tumor cells resulted in a potent inhibition of metastases formation, whereas IFN-gamma expression either did not affect or even enhanced the metastatic behavior of TS/A cells. These results provide strong evidence for the usefulness of IFN-alpha-producing tumor cells for the development of gene therapy strategies and vaccines against metastatic tumors.
Laboratory of Virology, Higher Institute of Health, Rome, Italy.
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M
Ferrantini
M
M
Giovarelli
A
A
Modesti
P
P
Musiani
A
A
Modica
M
M
Venditti
E
E
Peretti
P L
PL
Lollini
P
P
Nanni
G
G
Forni
D000230:Adenocarcinoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy / Q000648:ultrastructure; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015316:Genetic Therapy; D006183:H-2 Antigens / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D006183:H-2 Antigens; D016898:Interferon-alpha; D007371:Interferon-gamma