Enhanced in vivo sensitivity of in vitro interferon-treated B16 melanoma cells to CD8 cells and activated macrophages

Mouse B16 melanoma cells maintained in vitro in the presence of interferon (IFN)-alpha become resistant to the in vitro antiproliferative effects of IFN-alpha. However, IFN-alpha-treated mice inoculated with these in vitro IFN-treated cells (B16 alpha(res) cells) have significantly increased life spans (ILS) and significantly higher cure rates than IFN-alpha-treated mice inoculated with B16 cells, This unexpectedly greater sensitivity of B16 alpha(res) cells to the in vivo antitumor effects of IFN-alpha was evaluated by in vivo cell depletion experiments, Depletion of either activated peritoneal macrophages or cytotoxic T lymphocytes (CTL) reduced the ILS of IFN-treated B16 alpha(res)-inoculated mice to a level comparable to that of IFN-treated B16-inoculated mice, Depletion of natural killer (NK) cells did not affect the ILS for IFN-treated B16 alpha(res)-inoculated mice. These studies indicate that activated macrophage and CD8 cell function, but not NK cell function, is important for the enhanced antitumor effects induced by IFN-alpha against B16 alpha(res) cells, Macrophage killing was unlikely to be mediated by TNF-alpha or IL-1 as B16 and B16 alpha(res) cells were equally sensitive to TNF-alpha and insensitive to IL-1 in vitro, Further, H-2K antigen expression is significantly more readily inducible on B16 alpha(res) cells than on B16 cells, consistent with enhanced CDS-mediated killing due to increased MHC class I antigen expression.