Retroviral gene transfer induced constitutive expression of interleukin-2 or interferon-gamma in irradiated human melanoma cells.
Cytokines are important modulators of host antitumor responses. Two of these cytokines, interleukin-2 (IL-2) and interferon gamma (IFN-gamma), are produced after antigen-induced activation of helper lymphocytes. The cytokines are released into the immediate vicinity where they either interact with the appropriate receptors on effector cell populations or are rapidly degraded. To mimic this physiologic release of cytokines at the effector-target site, we used retroviral vectors to transduce melanoma cells with the IL-2 or IFN-gamma cDNA. Five melanoma cell lines were transduced with IL-2- or IFN-gamma-containing vectors and secreted IL-2 at 1 to 40 U/mL/10(6) cells/24 h or IFN-gamma 1 to 8 U/mL/10(6) cells/24 h, respectively. After gamma irradiation, these cells continued to secrete cytokines for about 3 to 4 weeks. Secretion of IFN-gamma induced upregulation of major histocompatibility complex class I molecules in a subset of melanoma cell lines. IL-2 production by human melanoma xenografts induced tumor rejection in BALB/c nu/nu mice, showing the in vivo effect of this cytokine. This study shows that (1) human melanoma cells can be stably transduced with cytokine-containing retroviral vectors; (2) cytokines are secreted constitutively by the transduced tumor cells and have the expected biologic effects in vitro and in vivo; and (3) after gamma irradiation, cytokines continue to be secreted for several weeks. These data suggest that irradiated cytokine-secreting allogenic or autologous tumor cells can be used in vaccination protocols for cancer patients.
Gansbacher
B
B
Division of Hematologic Oncology and Molecular Biology, Memorial-Sloan Kettering Cancer Center, New York, NY 10021.
Zier
K
K
Cronin
K
K
Hantzopoulos
P A
PA
Bouchard
B
B
Houghton
A
A
Gilboa
E
E
Golde
D
D
D016475:3T3 Cells; D000243:Adenosine Deaminase / Q000235:genetics; D000818:Animals; D002292:Carcinoma, Renal Cell; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D007376:Interleukin-2 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D007680:Kidney Neoplasms; D007700:Kinetics; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D007371:Interferon-gamma; D000243:Adenosine Deaminase