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Published on: November 28, 2019
TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage
Yuki Kaduka1, Kazuyoshi Takeda, Masafumi Nakayama
1Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp
Abstract:
TWEAK induces diverse cellular responses, including pro-inflammatory chemokine production, migration, proliferation, and cell death through the TWEAK receptor, Fn14. In the present study, we examined the effect of TWEAK or Fn14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion. In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn14. On the other hand, TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth. These results indicate that TWEAK mediates anti-tumor effect of macrophages in vivo.
Insights
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) exhibits an anti-tumor effect mediated by macrophages. Blocking TWEAK promotes tumor growth, highlighting TWEAK
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are involved in various cellular processes, including inflammation and cell death.
- The role of TWEAK and Fn14 in tumor immunity and progression remains incompletely understood.
Purpose of the Study:
- To investigate the impact of TWEAK and Fn14 expression within tumor cells on tumor development in vivo.
- To elucidate the mechanisms by which TWEAK influences anti-tumor immunity, particularly the role of macrophages.
Main Methods:
- Utilized neutralizing anti-TWEAK monoclonal antibody (mAb) in mouse models with TWEAK-sensitive and TWEAK-resistant tumor cells.
- Assessed tumor rejection frequency, survival rates, and tumor growth following anti-TWEAK mAb administration.
- Investigated the involvement of macrophage infiltration and Natural Killer (NK) cell activity by inhibiting macrophage infiltration and depleting NK cells.
Main Results:
- Neutralizing anti-TWEAK mAb reduced tumor rejection and survival in mice inoculated with TWEAK-sensitive, Fn14-expressing tumor cells.
- Anti-TWEAK mAb treatment promoted subcutaneous tumor growth, an effect abrogated by inhibiting macrophage infiltration but not by NK cell depletion.
- TWEAK expression in tumor cells did not significantly affect tumor growth, and anti-TWEAK mAb had no effect on TWEAK-resistant tumors.
Conclusions:
- TWEAK plays a crucial role in mediating the anti-tumor effects of macrophages in vivo.
- Blocking TWEAK can promote tumor growth by impairing macrophage-mediated anti-tumor responses.
- Targeting TWEAK may represent a therapeutic strategy in certain cancer contexts, potentially by modulating macrophage activity.
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