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bioRxiv · 10.1101/2025.03.04.640087

Translating Genetics into Tissue: Inflammatory Cytokine-Producing TAMs and PD-L1 Tumor Expression as Poor Prognosis Factors in Cutaneous Melanoma

Barrio-Alonso, C.·Nieto-Valle, A.·Barandalla-Revilla, L.·Aviles-Izquierdo, J. A.·Parra-Blanco, V.·Sanchez-Mateos, P.·Samaniego, R.
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Abstract

Myeloid cells within tumor microenvironments exhibit significant heterogeneity and play a critical role in influencing clinical outcomes. In this study, we investigated the infiltration of various myeloid cell subtypes in a cohort of cutaneous melanomas, revealing no significant correlation between myeloid cell densities and the occurrence of distant metastasis. We further examined the phenotypic characteristics of primary melanoma tumor-associated macrophages (TAMs) utilizing the seven-phenotype classification recently proposed by Ma et al., derived from extensive pan-cancer single-cell RNA-sequencing studies. First, we analyzed the transcriptomic profile of TAMs isolated from stage IV metastasizing primary melanomas, alongside melanoma-conditioned monocytes cultured in vitro, both supporting the inflammatory cytokine-producing macrophage phenotype. Next, we employed multicolor fluorescence confocal microscopy, to assess the expression of TAM phenotype markers at the protein level in a cohort of primary melanoma samples. Notably, markers indicative of the inflammatory TAM phenotype, quantified at single-cell level, were significantly enriched in metastasizing tumors, demonstrating an independent correlation with shorter disease-free and overall survival (log-rank test, p< 0.0002). Additionally, our screening of phenotype markers expression revealed that PD-L1 positivity in tumor cells, rather than in TAMs, was associated with poor prognosis, highlighting a novel aspect of the immune landscape in cutaneous melanoma.

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Barrio-Alonso, C., Nieto-Valle, A., Barandalla-Revilla, L., Aviles-Izquierdo, J. A., Parra-Blanco, V., Sanchez-Mateos, P., Samaniego, R.. 2025-03-07. Translating Genetics into Tissue: Inflammatory Cytokine-Producing TAMs and PD-L1 Tumor Expression as Poor Prognosis Factors in Cutaneous Melanoma. https://doi.org/10.1101/2025.03.04.640087

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