Indomethacin sensitizes resistant transformed cells to macrophage cytotoxicity

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.