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Suppression of macrophage antimicrobial activity by a tumor cell product
Abstract:
Medium conditioned by tumor cells (TCM) and certain nonmalignant cells contains a trypsin-sensitive factor that suppresses macrophage oxidative metabolism. Because the killing of intracellular pathogens such as Toxoplasma gondii and Leishmania donovani by macrophages is largely oxygen-dependent, we tested the effect of TCM on the antiprotozoal activity of mouse peritoneal macrophages. After 24 hr of cultivation with TCM, in vivo and in vitro activated macrophages could no longer kill toxoplasmas or inhibit their replication. In vivo administration of TCM resulted in similar impairment. The leishmanicidal activity of resident and activated macrophages, when measured 6 hr after infection, was markedly suppressed by in vitro exposure to TCM. The addition of exogenous H2O2 in the form of glucose-glucose oxidase reconstituted the capacity of TCM-exposed macrophages to kill L. donovani promastigotes as quickly as control cells. Thus, TCM appears to deactivate macrophages by the functional criteria of suppressed antitoxoplasmal and antileishmanial activity, as well as by the biochemical criterion of suppressed oxidative metabolism.
Insights
Tumor-conditioned medium (TCM) suppresses macrophage oxidative metabolism, impairing their ability to kill protozoan pathogens like Toxoplasma gondii and Leishmania donovani. This deactivation highlights a novel immune evasion strategy by tumor cells.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Macrophages are crucial immune cells for combating intracellular pathogens.
- Tumor cells can secrete factors that modulate the immune microenvironment.
- Macrophage antimicrobial activity is often dependent on oxidative metabolism.
Purpose of the Study:
- To investigate the effect of tumor-conditioned medium (TCM) on macrophage antimicrobial functions.
- To determine if TCM suppresses the oxidative metabolism of macrophages.
- To assess the impact of TCM on macrophage killing of protozoan parasites.
Main Methods:
- Macrophages were cultured in TCM derived from tumor cells.
- Antiprotozoal activity against Toxoplasma gondii and Leishmania donovani was assessed.
- Macrophage oxidative metabolism was evaluated.
- The effect of exogenous hydrogen peroxide (H2O2) was tested.
Main Results:
- TCM significantly suppressed the ability of macrophages to kill and inhibit the replication of Toxoplasma gondii.
- Leishmanicidal activity of macrophages against Leishmania donovani was markedly suppressed by TCM exposure.
- TCM impaired macrophage oxidative metabolism, a key component of their antimicrobial function.
- Restoration of hydrogen peroxide levels reconstituted the killing capacity of TCM-exposed macrophages.
Conclusions:
- Tumor-conditioned medium (TCM) deactivates macrophages, compromising their ability to fight protozoan infections.
- TCM-induced suppression of macrophage oxidative metabolism is a key mechanism underlying this deactivation.
- These findings suggest a potential immune evasion mechanism employed by tumor cells to escape host immune responses.