Abstract
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.
Highlights
METHODSMelanoma tumor is constituted by cancer cells and noncancerous cells including immune cells, mesenchymal stem cells, niche cells, cancer-associated fibroblasts, and adipocytes as well as the blood and lymphatic vascular systems, the extracellular matrix (ECM), and signaling molecules, which define the tumor microenvironment (Wang et al, 2017)
The altered metabolism of cancer cells influences the nutrient composition of the tumor microenvironment and as a consequence can modulate the anti-tumoral activity of immune cells (Lyssiotis and Kimmelman, 2017; Avagliano et al, 2020a,b)
Among the classes of metabolites analyzed, monophosphate and diphosphate nucleotides resulted enriched in Tumor interstitial fluid (TIF) compared to plasma samples (Figure 1D)
Summary
Melanoma tumor is constituted by cancer cells and noncancerous cells including immune cells, mesenchymal stem cells, niche cells, cancer-associated fibroblasts, and adipocytes as well as the blood and lymphatic vascular systems, the extracellular matrix (ECM), and signaling molecules, which define the tumor microenvironment (Wang et al, 2017). The altered metabolism of cancer cells influences the nutrient composition of the tumor microenvironment (e.g., glucose, lactate, Krebs cycle metabolites, amino acids) and as a consequence can modulate the anti-tumoral activity of immune cells (Lyssiotis and Kimmelman, 2017; Avagliano et al, 2020a,b). By altering the metabolic status of immune cells, tumors are able to elicit immune dysfunctions, including the aberrant production of cytokines, altered cytotoxicity, and macrophages polarization toward pro-tumoral phenotypes (Ho et al, 2015; Gonzalez et al, 2018)
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