Tumor necrosis factor-related, apoptosis-inducing ligand supports growth of mouse mastocytoma tumors by killing tumor-infiltrating macrophages.
TRAIL antisense transfected mastocytoma cells (R56VTas) injected into syngeneic DBA/2 mice demonstrate significantly delayed tumor growth compared to mock transfected cells (R56VTMo). TRAIL expression in R56VTas cells was successfully, albeit not completely, downregulated, as shown by Western blots, flow-cytometric analysis and functionally by loss of cytolytic activity against TRAIL-R-bearing target cells. Immunohistochemic and immunoblotting analyses of ex vivo tumors confirmed the lower expression of TRAIL by the antisense transfection compared to the mock transfection. Investigating the mechanism of the delayed tumor growth, it was found that neither T nor NK cells but activated macrophages infiltrated the tumors. The number of infiltrating macrophages was significantly lower in the mock transfected compared to the TRAIL antisense transfected tumor sections, indicating that TRAIL-expressing tumor cells may lyse macrophages. Indeed, activated macrophages proved to be sensitive to TRAIL-mediated apoptosis. This indicates that, although macrophages can infiltrate the mastocytoma R56VT, they are in part eliminated by TRAIL-expressing tumor cells, allowing the tumor to rapidly grow. Hence, downregulation of TRAIL allows more macrophages to survive and to better attack the tumor cells, slowing down tumor growth. In conclusion, TRAIL expressed on R56VT tumor cells can impair an important innate immune defense mechanism against tumors by eliminating effector macrophages.
Strebel
Alessandro
A
Institute for Medical Microbiology, University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
Bachmann
Felix
F
Wernli
Marion
M
Erb
Peter
P
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007377:Interleukin-3 / Q000378:metabolism; D019169:Jurkat Cells; D008264:Macrophages / Q000378:metabolism*; D012515:Mast-Cell Sarcoma / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D007377:Interleukin-3; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha