What question did this study set out to answer?

This study aims to explore the mechanisms by which nNOS and COX-2 interact in melanoma stimulated by interferon gamma.

April 5, 2026

Abstract 7464: Inhibiting interferon-gamma-stimulated melanoma progression by disrupting the crosstalk between nNOS/NO and COX-2

Puntos clave

This study aims to explore the mechanisms by which nNOS and COX-2 interact in melanoma stimulated by interferon gamma.
Conducted bioinformatic analysis of proteomic data related to IFN-γ in melanoma.
Utilized selective inhibitors (celecoxib and HH044) to assess their effects on melanoma progression.
Performed in vivo experiments using human melanoma xenograft mouse models.
Executed transcriptomic analysis post-treatment to evaluate gene expression changes.
Co-cultured human PBMCs with melanoma cells to assess T cell activation.
HH044 treatment significantly reduced tumor PGE2 levels in mouse models.
Combined treatment with HH044 and celecoxib lowered tumor volume to 19%, outperforming single treatments.
Transcriptomic analysis showed significant alterations in genes linked to matrix remodeling and metastasis after HH044 treatment.
HH044 pretreatment reactivated PBMCs, increasing IL-2+ T cell counts after co-incubation with melanoma cells.
Identified a positive feedback mechanism linking nNOS signaling to the COX-2/PGE2 axis in melanoma.

Resumen

Abstract Interferon gamma (IFN-γ) in the melanoma tumor microenvironment plays opposing roles, orchestrating both pro-tumorigenic activity and anticancer immune responses. Our previous studies demonstrated the role of neuronal nitric oxide synthase (nNOS) in IFN-γ-stimulated melanoma progression. However, the underlying mechanism has not been well defined. Bioinformatic analysis of patient and cellular proteomic data was conducted to identify proteins of interest associated with IFN-γ treatment in melanoma. Our omics analysis revealed that the induction of COX-2 was significantly predictive of IFN-γ treatment in melanoma cells. In the presence of IFN-γ, PGE2 further enhanced PD-L1 expression and amplified the induction of nNOS, which increased intracellular NO levels. Cotreatment with celecoxib, a selective COX-2 inhibitor, effectively diminished these changes induced by PGE2. nNOS blockade using a selective small molecule inhibitor (HH044) efficiently inhibited IFN-γ-Induced PGE2 production and COX-2 expression in melanoma cells. STAT3 inhibitor napabucasin also inhibited COX-2 expression both in the presence and absence of IFN-γ. In vivo, HH044 treatment significantly reduced tumor PGE2 levels in a human melanoma xenograft mouse model (A375/Nu/Nu). Combination treatment with HH044 and celecoxib yielded the greatest tumor suppression in the syngeneic murine melanoma model (Cloudman S91/DBA/2), reducing tumor volume to 19% of control, compared to 38% and 52% with HH044 or celecoxib alone, respectively. Furthermore, transcriptomic analysis revealed significant changes in genes involved in matrix remodeling and metastasis after HH044 treatment. Ex vivo co-culturing human PBMCs with melanoma cells inhibited T cell activation, decreasing IL-2-secreting T cells in the presence and absence of IFN-γ. PBMCs from a significant portion of donors (64%) were reactivated by HH044 pretreatment, displaying a significant increase in IL-2+ T cells after coincubation with melanoma cells.Our study reveals a positive feedback loop linking nNOS-mediated NO signaling to the COX-2/PGE2 signaling axis in melanoma, thereby further enhancing the pro-tumorigenic activity of IFN-γ. Disrupting crosstalk between nNOS/NO and COX-2 with selective inhibitors effectively suppressed melanoma tumor growth, possibly by modulating the tumor immune microenvironment. Citation Format: Anika Patel, Kate Alison Lozada, Moom Roosan, Basir Syed, Jennifer Totonchy, Amardeep Awasthi, Richard B. Silverman, Sun Yang. Inhibiting interferon-gamma-stimulated melanoma progression by disrupting the crosstalk between nNOS/NO and COX-2 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7464.

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Cite This Study

Patel et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fde4a79560c99a0a437c https://doi.org/https://doi.org/10.1158/1538-7445.am2026-7464

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