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Updated: Mar 20, 2026
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Published on: April 6, 2022
Indomethacin sensitizes resistant transformed cells to macrophage cytotoxicity
Hana Totary-Jain1, Ronit Vogt Sionov2, Ruth Gallily3
1Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Abstract:
Activated macrophages are well known to exhibit anti-tumor properties. However, certain cell types show intrinsic resistance. Searching for a mechanism that could explain this phenomenon, we observed that the supernatant of resistant cells could confer resistance to otherwise sensitive tumor cells, suggesting the presence of a secreted suppressor factor. The effect was abolished upon dialysis, indicating that the suppressor factor has a low molecular weight. Further studies showed that prostaglandin E2 (PGE2) is secreted by the resistant tumor cells and that inhibition of PGE2 production by indomethacin, a cyclooxygenase (COX) inhibitor, eliminated the macrophage suppression factor from the supernatant, and sensitized the resistant tumor cells to macrophage cytotoxicity. This study emphasizes the important role of tumor-secreted PGE2 in escaping macrophage surveillance and justifies the use of COX inhibitors as an adjuvant for improving tumor immunotherapy.
Insights
Tumor cells resist macrophage attack by secreting prostaglandin E2 (PGE2). Inhibiting PGE2 production with COX inhibitors sensitizes tumors to macrophage-mediated anti-tumor immunity, improving immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Activated macrophages possess anti-tumor properties.
- Some tumor cells exhibit intrinsic resistance to macrophage-mediated killing.
- A secreted factor from resistant cells may confer resistance to sensitive cells.
Purpose of the Study:
- To identify the mechanism by which certain tumor cells resist macrophage-mediated cytotoxicity.
- To investigate the role of secreted factors in tumor immune evasion.
- To evaluate the therapeutic potential of targeting this resistance mechanism.
Main Methods:
- Supernatant transfer experiments from resistant to sensitive tumor cells.
- Dialysis to assess the molecular weight of the suppressor factor.
- Identification of prostaglandin E2 (PGE2) as the secreted suppressor factor.
- Inhibition of PGE2 production using indomethacin (a cyclooxygenase inhibitor).
- Assessment of tumor cell sensitivity to macrophage cytotoxicity after indomethacin treatment.
Main Results:
- Supernatant from resistant cells conferred resistance to sensitive cells, indicating a secreted suppressor factor.
- The suppressor activity was lost upon dialysis, suggesting a low molecular weight factor.
- Prostaglandin E2 (PGE2) was identified as the secreted suppressor factor.
- Indomethacin treatment abolished macrophage suppression and sensitized resistant tumor cells to macrophage cytotoxicity.
- Tumor-secreted PGE2 plays a critical role in evading macrophage surveillance.
Conclusions:
- Tumor-secreted prostaglandin E2 (PGE2) is a key mechanism for evading macrophage-mediated anti-tumor immunity.
- Inhibition of PGE2 production via cyclooxygenase (COX) inhibitors can overcome tumor resistance.
- COX inhibitors represent a promising adjuvant therapy to enhance the efficacy of tumor immunotherapy.
