IFN-gamma-dependent delay of in vivo tumor progression by Fas overexpression on murine renal cancer cells.
The role of Fas in the regulation of solid tumor growth was investigated. Murine renal carcinoma (Renca) cells were constitutively resistant to Fas-mediated killing in vitro, but exhibited increased expression of Fas and sensitivity to Fas-mediated killing after exposure to IFN-gamma and TNF. Transfected Renca cells overexpressing Fas were efficiently killed in vitro upon exposure to anti-Fas Ab (Jo2). When Fas-overexpressing Renca cells were injected into syngenic BALB/c mice, there was a consistent and significant delay in tumor progression, reduced metastasis, and prolonged survival that was not observed for Renca cells that overexpressed a truncated nonfunctional Fas receptor. The delay of in vivo tumor growth induced by Fas overexpression was not observed in IFN-gamma-/- mice, indicating that IFN-gamma is required for the delay of in vivo tumor growth. However, there was a significant increase of infiltrated T cells and in vivo apoptosis in Fas-overexpressing Renca tumors, and Fas-overexpressing Renca cells were also efficiently killed in vitro by T cells. In addition, a strong therapeutic effect was observed on Fas-overexpressing tumor cells by in vivo administration of anti-Fas Ab, confirming that overexpressed Fas provides a functional target in vivo for Fas-specific ligands. Therefore, our findings demonstrate that Fas overexpression on solid tumor cells can delay tumor growth and provides a rationale for therapeutic manipulation of Fas expression as a means of inducing tumor regression in vivo.
Lee
J K
JK
Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Sayers
T J
TJ
Brooks
A D
AD
Back
T C
TC
Young
H A
HA
Komschlies
K L
KL
Wigginton
J M
JM
Wiltrout
R H
RH
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D004357:Drug Synergism; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000502:physiology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000502:physiology
D007106:Immune Sera; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma