CCL20/TNF/VEGFA Cytokine Secretory Phenotype of Tumor-Associated Macrophages Is a Negative Prognostic Factor in Cutaneous Melanoma



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Gutiérrez Seijo, Alba and García Martínez, Elena and Barrio Alonso, Celia and Pareja Malagón, Miriam and Acosta Ocampo, Alejandra and Fernández Santos, María Eugenia and Puig Kröger, Amaya and Parra Blanco, Verónica and Mercader, Enrique and Márquez Rodas, Iván and Avilés Izquierdo, José Antonio and Samaniego, Rafael and Sánchez-Mateos Rubio, Paloma (2021) CCL20/TNF/VEGFA Cytokine Secretory Phenotype of Tumor-Associated Macrophages Is a Negative Prognostic Factor in Cutaneous Melanoma. Cancers, 13 (16). p. 3943. ISSN 2072-6694

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TAMs constitute a large fraction of infiltrating immune cells in melanoma tissues, but their significance for clinical outcomes remains unclear. We explored diverse TAM parameters in clinically relevant primary cutaneous melanoma samples, including density, location, size, and polarization marker expression; in addition, because cytokine production is a hallmark of macrophages function, we measured CCL20, TNF, and VEGFA intracellular cytokines by single-cell multiparametric confocal microscopy. The Kaplan–Meier method was used to analyze correlation with melanoma-specific disease-free survival and overall survival. No significant correlations with clinical parameters were observed for TAM density, morphology, or location. Significantly, higher contents of the intracellular cytokines CCL20, TNF, and VEGFA were quantified in TAMs infiltrating metastasizing compared to non-metastasizing skin primary melanomas (p < 0.001). To mechanistically explore cytokine up-regulation, we performed in vitro studies with melanoma-conditioned macrophages, using RNA-seq to explore involved pathways and specific inhibitors. We show that p53 and NF-κB coregulate CCL20, TNF, and VEGFA in melanoma-conditioned macrophages. These results delineate a clinically relevant pro-oncogenic cytokine profile of TAMs with prognostic significance in primary melanomas and point to the combined therapeutic targeting of NF-kB/p53 pathways to control the deviation of TAMs in melanoma.

Item Type:Article
Uncontrolled Keywords:CCL20; TNF; VEGFA; melanoma; metastasis; TAM; biomarker; prognostic factor
Subjects:Medical sciences > Medicine > Medical genetics
Medical sciences > Medicine > Dentistry
ID Code:70887
Deposited On:02 Mar 2022 14:46
Last Modified:03 Mar 2022 09:05

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