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Macrophage nitric oxide synthesis delays progression of ultraviolet light-induced murine skin cancers
C Y Yim1, N R Bastian, J C Smith
1University of Utah Cancer Immunotherapy Program, Salt Lake City 84132.
Abstract:
The role of macrophages in the host immune response against cancers remains uncertain. Since nitric oxide synthesis represents a significant macrophage antitumor mechanism in vitro, we evaluated whether NO was synthesized during the immune response to growing murine skin cancers. NO synthesis was readily detectable in enzymatically dissociated tumors (RD-995 and LR-298) and was inhibited by N omega-monomethyl-L-arginine (MLA) and by macrophage depletion. Nitrosylation of iron-sulfur and heme complexes was observed in these tumors using electron paramagnetic resonance spectroscopy. NO production in the presence of increasing concentrations of MLA correlated inversely with tumor cell proliferation in vitro. To elucidate the role of NO during in vivo tumor progression, tumor-bearing mice were treated with continuous infusions of the nitric oxide synthase inhibitor MLA. MLA-treated mice demonstrated increased growth and delayed rejection of the highly antigenic UV radiation-induced regressor tumor LR-298. These experiments demonstrate that macrophage-derived NO synthesis can contribute to the antitumor immune response in vivo.
Insights
Macrophages synthesize nitric oxide (NO), a key antitumor mechanism. This study shows NO production in murine skin cancers, with inhibition leading to increased tumor growth, demonstrating NO
Area of Science:
- Immunology
- Cancer Research
- Biochemistry
Background:
- The precise role of macrophages in anti-cancer immunity is unclear.
- Nitric oxide (NO) produced by macrophages is a known in vitro antitumor mechanism.
Purpose of the Study:
- To investigate NO synthesis during the immune response to murine skin cancers.
- To determine the in vivo role of NO in tumor progression.
Main Methods:
- Detection of NO synthesis in murine skin tumors (RD-995 and LR-298).
- Inhibition of NO synthesis using N omega-monomethyl-L-arginine (MLA).
- Assessment of tumor cell proliferation and in vivo tumor progression in MLA-treated mice.
- Electron paramagnetic resonance spectroscopy to detect nitrosylation of iron-sulfur and heme complexes.
Main Results:
- NO synthesis was detectable in tumors and inhibited by MLA and macrophage depletion.
- In vitro, NO production inversely correlated with tumor cell proliferation.
- In vivo, MLA treatment led to increased tumor growth and delayed rejection of the LR-298 tumor.
- Nitrosylation of iron-sulfur and heme complexes was observed in tumors.
Conclusions:
- Macrophage-derived NO contributes to the in vivo antitumor immune response.
- Inhibition of NO synthesis enhances tumor progression in murine models.