Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth
Tumor interstitial fluid (TIF) surrounds and perfuses tumors and collects ions, metabolites, proteins, and extracellular vesicles secreted by tumor and stromal cells. Specific metabolites, accumulated within the TIF, could induce metabolic alterations of immune cells and shape the tumor microenviron...
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.730726/full |
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| author | Eleonora Vecchio Carmen Caiazza Selena Mimmi Angelica Avagliano Enrico Iaccino Teresa Brusco Nancy Nisticò Domenico Maisano Annamaria Aloisio Ileana Quinto Maurizio Renna Giuseppina Divisato Simona Romano Martina Tufano Massimo D’Agostino Elena Vigliar Antonino Iaccarino Chiara Mignogna Francesco Andreozzi Gaia Chiara Mannino Rosangela Spiga Mariano Stornaiuolo Alessandro Arcucci Massimo Mallardo Giuseppe Fiume |
| author_facet | Eleonora Vecchio Carmen Caiazza Selena Mimmi Angelica Avagliano Enrico Iaccino Teresa Brusco Nancy Nisticò Domenico Maisano Annamaria Aloisio Ileana Quinto Maurizio Renna Giuseppina Divisato Simona Romano Martina Tufano Massimo D’Agostino Elena Vigliar Antonino Iaccarino Chiara Mignogna Francesco Andreozzi Gaia Chiara Mannino Rosangela Spiga Mariano Stornaiuolo Alessandro Arcucci Massimo Mallardo Giuseppe Fiume |
| author_sort | Eleonora Vecchio |
| collection | DOAJ |
| description | Tumor interstitial fluid (TIF) surrounds and perfuses tumors and collects ions, metabolites, proteins, and extracellular vesicles secreted by tumor and stromal cells. Specific metabolites, accumulated within the TIF, could induce metabolic alterations of immune cells and shape the tumor microenvironment. We deployed a metabolomic approach to analyze the composition of melanoma TIF and compared it to the plasma of C57BL6 mice, engrafted or not with B16-melanoma cells. Among the classes of metabolites analyzed, monophosphate and diphosphate nucleotides resulted enriched in TIF compared to plasma samples. The analysis of the effects exerted by guanosine diphosphate (GDP) and uridine diphosphate (UDP) on immune response revealed that GDP and UDP increased the percentage of CD4+CD25+FoxP3– and, on isolated CD4+ T-cells, induced the phosphorylation of ERK, STAT1, and STAT3; increased the activity of NF-κB subunits p65, p50, RelB, and p52; increased the expression of Th1/Th17 markers including IFNγ, IL17, T-bet, and RORγt; and reduced the expression of IL13, a Th2 marker. Finally, we observed that local administrations of UDP in B16-engrafted C57BL6 mice reduced tumor growth and necrotic areas. In addition, UDP-treated tumors showed a higher presence of MHCIIhi tumor-associated macrophage (TAM) and of CD3+CD8+ and CD3+CD4+ tumor-infiltrating T-lymphocytes (TILs), both markers of anti-tumor immune response. Consistent with this, intra-tumoral gene expression analysis revealed in UDP-treated tumors an increase in the expression of genes functionally linked to anti-tumor immune response. Our analysis revealed an important metabolite acting as mediator of immune response, which could potentially represent an additional tool to be used as an adjuvant in cancer immunotherapy. |
| first_indexed | 2024-12-13T20:19:35Z |
| format | Article |
| id | doaj.art-e0952c261d734b00afde09bb9203f215 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-13T20:19:35Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-e0952c261d734b00afde09bb9203f2152022-12-21T23:32:44ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-09-01910.3389/fcell.2021.730726730726Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor GrowthEleonora Vecchio0Carmen Caiazza1Selena Mimmi2Angelica Avagliano3Enrico Iaccino4Teresa Brusco5Nancy Nisticò6Domenico Maisano7Annamaria Aloisio8Ileana Quinto9Maurizio Renna10Giuseppina Divisato11Simona Romano12Martina Tufano13Massimo D’Agostino14Elena Vigliar15Antonino Iaccarino16Chiara Mignogna17Francesco Andreozzi18Gaia Chiara Mannino19Rosangela Spiga20Mariano Stornaiuolo21Alessandro Arcucci22Massimo Mallardo23Giuseppe Fiume24Department of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Public Health, University of Naples Federico II, Naples, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Public Health, University of Naples Federico II, Naples, ItalyDepartment of Public Health, University of Naples Federico II, Naples, ItalyDepartment of Health Sciences, Magna Graecia University, Catanzaro, ItalyDepartment of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, ItalyDepartment of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, ItalyDepartment of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, ItalyDepartment of Pharmacy, University of Napoli Federico II, Naples, ItalyDepartment of Public Health, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Experimental and Clinical Medicine, University of Catanzaro “Magna Graecia”, Catanzaro, ItalyTumor interstitial fluid (TIF) surrounds and perfuses tumors and collects ions, metabolites, proteins, and extracellular vesicles secreted by tumor and stromal cells. Specific metabolites, accumulated within the TIF, could induce metabolic alterations of immune cells and shape the tumor microenvironment. We deployed a metabolomic approach to analyze the composition of melanoma TIF and compared it to the plasma of C57BL6 mice, engrafted or not with B16-melanoma cells. Among the classes of metabolites analyzed, monophosphate and diphosphate nucleotides resulted enriched in TIF compared to plasma samples. The analysis of the effects exerted by guanosine diphosphate (GDP) and uridine diphosphate (UDP) on immune response revealed that GDP and UDP increased the percentage of CD4+CD25+FoxP3– and, on isolated CD4+ T-cells, induced the phosphorylation of ERK, STAT1, and STAT3; increased the activity of NF-κB subunits p65, p50, RelB, and p52; increased the expression of Th1/Th17 markers including IFNγ, IL17, T-bet, and RORγt; and reduced the expression of IL13, a Th2 marker. Finally, we observed that local administrations of UDP in B16-engrafted C57BL6 mice reduced tumor growth and necrotic areas. In addition, UDP-treated tumors showed a higher presence of MHCIIhi tumor-associated macrophage (TAM) and of CD3+CD8+ and CD3+CD4+ tumor-infiltrating T-lymphocytes (TILs), both markers of anti-tumor immune response. Consistent with this, intra-tumoral gene expression analysis revealed in UDP-treated tumors an increase in the expression of genes functionally linked to anti-tumor immune response. Our analysis revealed an important metabolite acting as mediator of immune response, which could potentially represent an additional tool to be used as an adjuvant in cancer immunotherapy.https://www.frontiersin.org/articles/10.3389/fcell.2021.730726/fullmetabolite profilingTIL (tumor infiltrating lymphocytes)anti-tumor immunityB16 engraftmentUDP |
| spellingShingle | Eleonora Vecchio Carmen Caiazza Selena Mimmi Angelica Avagliano Enrico Iaccino Teresa Brusco Nancy Nisticò Domenico Maisano Annamaria Aloisio Ileana Quinto Maurizio Renna Giuseppina Divisato Simona Romano Martina Tufano Massimo D’Agostino Elena Vigliar Antonino Iaccarino Chiara Mignogna Francesco Andreozzi Gaia Chiara Mannino Rosangela Spiga Mariano Stornaiuolo Alessandro Arcucci Massimo Mallardo Giuseppe Fiume Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth Frontiers in Cell and Developmental Biology metabolite profiling TIL (tumor infiltrating lymphocytes) anti-tumor immunity B16 engraftment UDP |
| title | Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth |
| title_full | Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth |
| title_fullStr | Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth |
| title_full_unstemmed | Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth |
| title_short | Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth |
| title_sort | metabolites profiling of melanoma interstitial fluids reveals uridine diphosphate as potent immune modulator capable of limiting tumor growth |
| topic | metabolite profiling TIL (tumor infiltrating lymphocytes) anti-tumor immunity B16 engraftment UDP |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.730726/full |
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