IFN-γ-Dependent Delay of In Vivo Tumor Progression by Fas Overexpression on Murine Renal Cancer Cells

• DOI: 10.4049/jimmunol.164.1.231
• Publication Date: 2014-04-21T22:07:57Z
• Authors: Jong-Keuk Lee; Thomas J. Sayers; Alan D. Brooks; Timothy C. Back; Howard A. Young; Kristin L. Komsch...; Jon M. Wigginton; Robert H. Wiltrout
• Keywords: Mice, Knockout; Mice, Inbred BALB C; Time Factors; Tumor Necrosis Factor-alpha; Immune Sera; T-Lymphocytes; Apoptosis; Drug Synergism; Adenocarcinoma; Injections, Intralesional; Immunity, Innate; Kidney Neoplasms; Recombinant Proteins; Up-Regulation; 3. Good health; Interferon-gamma; Mice; 03 medical and health sciences; 0302 clinical medicine; Tumor Cells, Cultured; Animals; Cell Division; Sequence Deletion

AbstractThe 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-γ 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-γ−/− mice, indicating that IFN-γ 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.