IFN-α-Expressing Tumor Cells Enhance Generation and Promote Survival of Tumor-Specific CTLs

Abstract IFN-α gene therapy has been successfully applied in several tumor models. Our studies involving the murine colorectal adenocarcinoma cell line MC38 confirm that IFN-α transduction of a poorly immunogenic tumor cell reduces tumorigenicity and leads to long-lasting tumor immunity. To investigate the effect of IFN-α transduction on the development of antitumor immune responses, we restimulated splenocytes from MC38-immune mice in vitro. Detection of MC38-specific cytotoxicity was markedly enhanced when murine IFN-α2-transduced MC38 (MC38-IFNα) or CD80-transduced MC38 (MC38-CD80) was used for restimulation compared with wild type (MC38-WT) or neomycin resistance gene-transduced MC38 (MC38-Neo) cells. MC38-specific CD8+ CTL line and clone were established from splenocytes of mouse immunized with MC38-IFNα. Stimulation with MC38-IFNα as well as MC38-CD80 enhanced the proliferation of MC38-specific CTLs in vitro much more effectively than stimulation with WT or MC38-Neo (p < 0.05). Coincubation of MC38-specific CTLs with MC38-IFNα or MC38-CD80 resulted in significantly less DNA fragmentation (8.0% and 12.8%, respectively) compared with coincubation of the CTLs with MC38-WT (43.5%; p < 0.001) or MC38-Neo cells (38.1%; p < 0.003). These results suggest that prevention of apoptotic cell death in tumor-specific CTLs may be one mechanism by which IFN-α-expressing tumor cells can promote the generation of antitumor immunity. The effect of IFN-α on CTLs appears to be similar to that of CD80, which also prevents apoptotic cell death after stimulation of T lymphocytes.