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Tumor necrosis factor–related, apoptosis‐inducing ligand supports growth of mouse mastocytoma tumors by killing tumor‐infiltrating macrophages
Author(s) -
Strebel Alessandro,
Bachmann Felix,
Wernli Marion,
Erb Peter
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10539
Subject(s) - mastocytoma , transfection , tumor necrosis factor alpha , biology , macrophage , cancer research , immune system , effector , apoptosis , cell culture , immunology , microbiology and biotechnology , in vitro , tumor cells , biochemistry , genetics
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. © 2002 Wiley‐Liss, Inc.