TRAIL-induced cell death cooperates with IFN-gamma activation in the graft-versus-tumor effect against colon tumors.
The graft-versus-tumor (GVT) effect that occurs following allogeneic bone marrow transplantation (BMT) and donor lymphocyte infusion (DLI) is currently being subjected to intensive investigation because of clinical evidence for GVT efficacy against leukemia. In this report, we investigate the efficacy and molecular mechanisms of GVT against solid tumors, using a modification of the mouse parent-to-F1 BMT model. Mouse Colon26 cells in which tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor expression was stably knocked down were transplanted to investigate the role of the TRAIL-TRAIL receptor system in the GVT effect. In addition, Fas ligand-(FasL) deficient mice on a C57BL6 (B6) background were used as donors, to determine the significance of the Fas-FasL system for the antitumor effect. The group that received B6 DLI followed by preconditioning with 950 rad irradiation underwent tumor reduction associated with the induction of IFN-gamma, TRAIL and tumor-cell apoptosis. In vitro cultured Colon26 cells were resistant to TRAIL but susceptible to the combination of IFN-gamma and TRAIL in a TRAIL-dose-dependent manner. The infusion of lymphocytes from FasL-defective donors reduced the tumor progression, although efficacy was decreased in the TRAIL receptor knockdown tumors but not in wild-type ones, compared with infusion of B6-derived lymphocytes. The findings indicate that GVT activity against subcutaneous colon tumors is efficiently induced by preconditioning with irradiation and allogeneic DLI, and that TRAIL and IFN-gamma act cooperatively in the antitumor effect.
Tateishi
Keisuke
K
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. ktate-tky@umin.ac.jp
Ohta
Miki
M
Guleng
Bayasi
B
Kanai
Fumihiko
F
Tanaka
Yasuo
Y
Asaoka
Yoshinari
Y
Jazag
Amarsanaa
A
Imamura
Jun
J
Imamura
Takaaki
T
Ijichi
Hideaki
H
Ikenoue
Tsuneo
T
Kawakami
Takayuki
T
Fukushima
Yasushi
Y
Washida
Miwa
M
Sata
Masataka
M
Miyagishi
Makoto
M
Taira
Kazunari
K
Yoshida
Haruhiko
H
Kawabe
Takao
T
Omata
Masao
M
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D016026:Bone Marrow Transplantation; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005260:Female; D020350:Graft vs Tumor Effect / Q000235:genetics*; D007371:Interferon-gamma / Q000502:physiology*; D017710:Lymphocyte Transfusion; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D048069:Tumor Necrosis Factors
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma