SummaryDBA/2 mice were injected intravenously with 2 x 106 3C18 Friend erythroleukemia cells (FLC), a cell line resistant to interferon ac/R (IFN-a/a) . Although daily administration of mouse IFNcx/o markedly increased the mean survival time, most IFN-treated mice continued to harbor FLC in different organs . To investigate the mechanisms responsible for this persistent suppression of FLC growth in IFN-treated mice, we undertook a series of adoptive transfer experiments with sera and spleen cells. Sera from FLC-injected, IFN-treated mice were very effective in conferring protection on DBA/2 mice even when injected systemically (intravenously) 18-24 h before intravenous challenge with FLC. These sera also exhibited antitumor activity when injected subcutaneously or intraperitoneally together with FLC. The protective factor in serum was shown to be an immunogloblin . FLC-injected, IFN-treated mice developed antibodies to FLC demonstrable by radioimmunoassay and complement-dependent cytotoxicity. Sera from these mice recognized a specific 65-kD FLC membrane antigen(s) not detectable on membrane extracts from RBLr5 or ESb tumor cells, or on normal spleen cells . FLC-injected, IFN-treated mice also developed a specific cellular response demonstrable by transfer of protection with spleen cells injected intravenously or subcutaneously. Analysis of the responsible spleen cell populations indicated that the effector cells were neither T nor B cells . These results demonstrating the importance of host humoral and cellular immune mechanisms in the persistent suppression of FLC in IFNtreated mice may be relevant to the use of IFN-oi//3 in patients in whom tumors may regress and tumor cells may then remain latent for extended periods of time .W e have been interested in how IFN inhibits tumor growth and especially how it inhibits the development of tumor metastases . Using an experimental mouse model, we showed that IFN-a/(3 treatment was very effective in inhibiting the development of Friend erythroleukemia cell (FLC)t metastases and in increasing mouse survival time (1, 2). Use of IFN-ot//.-resistant lines of FLC indicated that IFN was most likely not acting directly on the tumor cells themselves (3-6), but acted through host mechanisms (1), and our previous experiments emphasized the importance of 1 Abbreviations used in this paper. FLC, Friend erythroleukemia cell ; NDV, Newcastle disease virus; VSV, vesicular stomatitis virus .an intact immune system in achieving optimal therapeutic effects (7) .In the months after injection of tumor cells, it became apparent that FLC often remained latent in different organs even after IFN treatment had been discontinued . These observations suggested that either the phenotype of tumorigenicity of residual FLC had changed or that IFN-treated mice developed means of restraining FLC tumor growth. As our experimental results showed that FLC recovered from the livers of surviving IFN-treated mice still conserved their tumorigenic and metastatic capacity, we investigated the nature of possi...