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Macrophage-mediated suppression of natural killer cell activity in mice bearing Lewis lung carcinoma
Abstract:
The natural killer (NK) cell cytotoxic capacity of C57BL/6 mice with implantation of Lewis lung carcinoma (LLC) was quantitated during tumor growth. The NK activity became suppressed at 1 week of tumor growth and remained suppressed. The mechanisms for the suppression during the first 3 weeks of tumor growth included secretion of prostaglandin E2 (PGE2) by both the LLC tumor and host macrophages. With tumor growth, plasma PGE2 concentrations progressively increased. Oral administration of indomethacin to tumor-bearing mice prevented the rise in serum PGE2 concentrations and the suppression of NK activity. Cultured LLC cells and splenic macrophages isolated from mice during the first 3 weeks of tumor growth secreted increased amounts of PGE2. Macrophages from tumor-bearer spleen cells were shown to suppress NK activity. Depletion of these macrophages restored the NK activity, and addition of these macrophages to normal spleen cells resulted in an indomethacin-sensitive suppression of the NK response. The mechanisms of suppression in mice bearing large tumors were different than those observed with smaller tumors. With a large tumor burden, the plasma PGE2 concentrations declined. Indomethacin treatment did not prevent the suppression of NK activity, and depletion of splenic macrophages did not restore NK cytotoxicity.
Insights
Tumor growth suppresses natural killer (NK) cell activity through prostaglandin E2 (PGE2) secretion. Indomethacin treatment and macrophage depletion restore NK cell function in early tumor stages, but not with large tumors.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Natural killer (NK) cells are crucial for anti-tumor immunity.
- Lewis lung carcinoma (LLC) implantation in C57BL/6 mice leads to suppressed NK cell activity.
- Understanding the mechanisms of NK cell suppression is vital for developing immunotherapies.
Purpose of the Study:
- To investigate the mechanisms of NK cell suppression during LLC tumor growth.
- To evaluate the role of prostaglandin E2 (PGE2) and macrophages in NK cell dysfunction.
- To assess the efficacy of indomethacin in restoring NK cell activity.
Main Methods:
- Quantitation of NK cell cytotoxic capacity in tumor-bearing mice.
- Measurement of PGE2 concentrations in plasma and cultured cells.
- Administration of indomethacin and assessment of its effects on NK activity and PGE2 levels.
- Macrophage depletion studies and functional assays.
Main Results:
- NK cell activity was suppressed starting one week after LLC implantation.
- Prostaglandin E2 (PGE2) secreted by LLC cells and host macrophages mediated suppression in early tumor stages.
- Oral indomethacin administration prevented increased PGE2 and NK cell suppression.
- Macrophages from tumor-bearing mice suppressed NK activity in an indomethacin-sensitive manner.
- In large tumors, PGE2 levels decreased, and indomethacin/macrophage depletion failed to restore NK activity, indicating different suppression mechanisms.
Conclusions:
- PGE2 and macrophages are key mediators of NK cell suppression in early-stage LLC tumors.
- Indomethacin can restore NK cell function by inhibiting PGE2 production.
- Tumor burden influences the mechanisms of NK cell suppression, with distinct pathways operating in late-stage disease.