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Integration of functional precision oncology testing defines immunotherapies strategies for mucosal melanomas.

ABSTRACT: Mucosal melanomas (MM) arise from mucosal melanocytes at different anatomical sites. MM are rare and highly aggressive, and their outcome is very poor. Only dismal clinical benefits have been obtained for the disseminated disease, with very limited promising results using approved immune checkpoint inhibitors. Compared to the cutaneous counterpart, data on the immunogenicity and IFN-γ sensitivity of MM are largely missing. Here, we explored these issues combining microscopy and -omics approaches on a set of unique sino-nasal melanoma (SN-MM) cell lines and clinical samples. All SN-MM cell lines display normal surface expression of IFNGR along with integrity of the IFNGR/JAK/STAT signaling pathway. Moreover, as a group, all SN-MM cell lines resulted responsive to the administration of IFN-γ as measured by transcriptomic and proteomic signatures. Specifically, IFN-γ induced canonical IFN-γ regulated genes involved in immune cell recognition and antigen presentation. In sixty percent of SN-MM cell lines IFN-γ also exerted a direct cytotoxic and anti-proliferative effect, release of CXCL10 and surface expression of CD274/PD-L1; the remaining fraction of SN-MM cell lines display IFN-γ functional refractoriness, likely dependent on post-transcriptional regulation of the IFN-γ regulated molecules. Analysis of clinical samples revealed that SN-MM are immune desert with scarce tumor-infiltrating lymphocytes (TILs), a feature predicting unfavourable outcomes; moreover, they resulted negative for CD274/PD-L1. This set of findings indicates that integration of functional precision oncology might refine the characterization of immune escape mechanisms to better allocate melanoma patients to various IT options.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mucosal Melanoma Cell

SUBMITTER: Marcello Manfredi

LAB HEAD: Marcello Manfredi

PROVIDER: PXD059186 | Pride | 2026-03-16

REPOSITORIES: Pride

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			Action	DRS
	FilePeak.zip	Other
	FileRaw.zip	Other
	Melanomi_Vermi_1_GHDO_CTRL_24h_2ugul_07092021_LIB1.mgf	Mgf
	Melanomi_Vermi_1_GHDO_CTRL_4h_09092021_LIB1.mgf	Mgf
	Melanomi_Vermi_1_GHDO_IFNY_4h_09092021_LIB1.mgf	Mgf

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Project description:Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD biosynthesis and is frequently upregulated in tumors, including melanoma, where it drives disease progression and resistance to targeted therapies. Beyond its metabolic role, NAMPT also exerts immune-modulatory functions, acting as a cytokine-like mediator that shapes tumor–host interactions and influences the efficacy of immunotherapy. Building on recent evidence indicating a connection between the pro-inflammatory cytokine interferon-gamma (IFN-γ) signaling and NAD metabolism, we sought to explore this poorly understood relationship in melanoma context. Analysis of the TCGA melanoma cohort revealed a significant correlation between NAMPT expression and IFN-γ signaling, including specific genes belonging to this pathway, such as IRF1, STAT1, and CD274/PD-L1. The correlation between NAMPT and PD-L1 was also confirmed at the protein level in more than 100 cases included in a melanoma tissue microarray (TMA). Functionally, IFN-γ treatment (100ng/ml for 24h) of three MM cell lines led to increased NAMPT transcription and intracellular expression, as well as increased release. Molecularly, as previously demonstrated for IFN-γ-inducible PD-L1, also NAMPT expression upon IFN-γ signaling activation is regulated at epigenetic/transcriptional level via bromodomain protein BRD4/IRF1 complex, as revealed using BRD4 inhibitors and chromatin immunoprecipitation (ChIP)-RT-PCR experiments. In the second part of our results, we showed a bidirectional regulation between NAD/NAMPT axis and IFN-γ signaling. NAMPT inhibition, as well as genetic silencing, reduced IFN-γ signaling activation, as highlighted by RNAseq data and confirmed by biochemical validation. This reciprocal regulation involved the modulation of mitochondrial respiration, specifically mitochondrial Complex I. Analysis of the melanoma TCGA cohort revealed a significant correlation between NAMPT expression, IFN signaling and several mitochondrial Complex I subunit genes. Consistently, activation of IFN-γ signaling in melanoma cell lines induced an increase in oxygen consumption rate, which was completely abrogated by NAD/NAMPT-dependent inhibition of complex I activity, indicating a direct metabolic crosstalk.

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Integration of functional precision oncology testing defines immunotherapies strategies for mucosal melanomas.

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