IFN-α-expressing tumor cells enhance generation and promote survival of tumor-specific CTLs

IFN-alpha gene therapy has been successfully applied in several tumor models. Our studies involving the murine colorectal adenocarcinoma cell line MC38 confirm that IFN-alpha transduction of a poorly immunogenic tumor cell reduces tumorigenicity and leads to long-lasting tumor immunity, To investigate the effect of IFN-alpha transduction on the development of antitumor immune responses, we restimulated splenocytes from MC38-inmune mice in vitro. Detection of MC38-specific cytotoxicity was markedly enhanced when murine IFN-alpha 2-transduced MC38 (MC38-IFN alpha) or CD80-transduced MC38 (MC38-CD80) was used for restimulation compared,vith 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-IFN alpha, Stimulation with MC38-IFN alpha 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 vith MC38-IFN alpha 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-alpha-expressing tumor cells can promote the generation of antitumor immunity. The effect of IFN-alpha on CTLs appears to be similar to that of CD80, which also prevents apoptotic cell death after stimulation of T lymphocytes.