Date of Award
Master of Science (MS)
The incidence of cutaneous melanoma (CM) rises despite advances in immunotherapy and targeted therapy. Studies have shown that interferon-gamma (IFN-γ), a pro-tumorigenic cytokine in CM, induces the expression of programmed death-ligand 1 (PD-L1), leading to the escape of melanoma cells from immunosurveillance. Our previous study suggests that neuronal nitric oxide synthase (nNOS)-mediated nitric oxide (NO) signaling is crucial for melanoma progression and forms a mechanistic rationale behind nNOS inhibition as a novel treatment strategy for CM. An additional study demonstrated that IFN-γ interacts with nNOS signaling in melanoma and novel nNOS inhibitors (nNOSi) effectively diminished the induction of PD-L1 post IFN-γ exposure. In this study, we determined the effects of nNOSi on melanoma-induced immunosuppression of T cells. Fresh whole blood samples were collected from 11 disease-free human donors (7 male, 10 Caucasian) between the ages of 20 – 40 years old. CD3+ T cells derived from peripheral blood mononuclear cells (PBMCs) were co-incubated with human metastatic melanoma cells in the presence or absence of IFN-γ (250 U/ml). A selective nNOSi MAC-3-190 was added to suppress nNOS-NO signaling in melanoma cells. IL-2+ T cells detected by flow cytometry represent the activation of CD4+ T cells and CD8+ T cells. Our ex vivo study demonstrated that co-incubation with melanoma significantly reduced the average relative percent of IL-2+ in CD4+ and CD8+ T cell populations to below 0.5-fold compared to T cell alone (p+ and CD8+ T cell populations remained inactivated when co-incubated with IFN-γ-treated melanoma cells as indicated by the decrease in IL-2+ T cells to 0.5-fold of control (p+ T cells as shown by the increase in IL-2+ T cells to 0.8-fold of control compared to IFN-γ-treated melanoma (p
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Lozada, KAJ. Effects of nNOS Inhibitors on Melanoma-Induced Immunosuppression. [master’s thesis]. Irvine, CA: Chapman University; 2022. https://doi.org/10.36837/chapman.000401
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