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-Expressing Tumor Cells Enhance Generation and Promote Survival of Tumor-Specific CTLs
*
Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261; and
Department of Dermatology, J. Gutenberg-University, Mainz, Germany
IFN-
gene therapy has been successfully applied in several tumor
models. Our studies involving the murine colorectal adenocarcinoma cell
line MC38 confirm that IFN- transduction of a poorly immunogenic
tumor cell reduces tumorigenicity and leads to long-lasting tumor
immunity. To investigate the effect of IFN- 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-2-transduced MC38
(MC38-IFN) 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-IFN. Stimulation with MC38-IFN 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-IFN 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--expressing tumor cells can promote the
generation of antitumor immunity. The effect of IFN- on CTLs appears
to be similar to that of CD80, which also prevents apoptotic cell death
after stimulation of T lymphocytes.
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