Interleukin-12 transduced dendritic cells induce regression of established murine neuroblastoma.
OBJECTIVE
Interleukin 12 (IL-12) is a potent proinflammatory cytokine that enhances cytotoxic T lymphocytes (CTL) and natural killer (NK) cell activity. The goal of these experiments was to assess whether adenoviral-mediated IL-12 expression by dendritic cells (DC) could induce an antitumor immune response in a murine model of neuroblastoma.


METHODS
Syngeneic A/J mice were inoculated subcutaneously with 1 x 10(6) cells from a murine neuroblastoma-derived cell line (TBJ). Murine DC were transduced in vitro with adCMV-mIL-12, and 1 x 10(6) cells were injected intratumorally. Tumor growth in these mice was compared with control animals injected with enhanced green-filled protein (EGFP) transduced DC or saline. The role of CTL was evaluated through cytotoxicity assays. Immunohistochemical analysis of tumor, spleen, and lymph node was performed to characterize the behavior and fate of various populations of immune effector cells in these tissues.


RESULTS
The tumors of mice injected with adIL-12 transduced DC all underwent complete regression over a 3-week period. Splenocytes isolated from mice 7 days after intratumoral injection of adIL-12 DC showed increased cytolytic activity relative to control animals in vitro. Immunohistochemistry of tumor and lymph tissue showed increased amounts of DC and T lymphocyte infiltration and a slight decrease in apoptosis relative to the control groups.


CONCLUSIONS
Increased IL-12 production by DC induced a significant antitumor response in a poorly immunogenic murine neuroblastoma model. These results show the vital role of DC in the immunobiology of the disease, and that protection of these cells from tumor induced apoptosis is a critical aspect for immunotherapies treating this aggressive tumor.
Shimizu
T
T
Department of Surgery, University of Pittsburgh School of Medicine, Division of Pediatric Surgery, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
Berhanu
A
A
Redlinger
R E
RE
Watkins
S
S
Lotze
M T
MT
Barksdale
E M
EM
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000473:pathology / Q000628:therapy*; D011336:Probability; D012016:Reference Values; D012074:Remission Induction; D012680:Sensitivity and Specificity
D018664:Interleukin-12