IFN-alpha-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-immune mice in vitro. Detection of MC38-specific cytotoxicity was markedly enhanced when murine IFN-alpha2-transduced MC38 (MC38-IFNalpha) 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-IFNalpha. Stimulation with MC38-IFNalpha 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-IFNalpha 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.
Hiroishi
K
K
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Tüting
T
T
Lotze
M T
MT
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019264:Adoptive Transfer; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology; D053938:DNA Fragmentation / Q000276:immunology; D004273:DNA, Neoplasm / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000276:immunology* / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D004273:DNA, Neoplasm; D018984:Epitopes, T-Lymphocyte; D016898:Interferon-alpha