Abstract
Hyperuricaemia is associated with various metabolic dysfunctions including obesity, type 2 diabetes mellitus, hypertension and in general metabolic syndrome, which are all associated with increased risk of cancer. However, the direct association between elevated uricemia and cancer mortality still remains unclear. In this study, we used a mouse model of hyperuricemia, the Urahplt2/plt2 (PLT2) mouse, to investigate the effect of high uric acid levels on anti-tumor immune responses and tumor growth. In normo-uricaemic C57BL/6 mice injected with B16 melanomas, immunotherapy by treatment with Poly I:C at the tumor site delayed tumor growth compared to PBS treatment. In contrast, Poly I:C-treated hyper-uricaemic PLT2 mice were unable to delay tumor growth. Conventional and monocyte-derived dendritic cells in the tumor-draining lymph nodes (dLN) of C57BL/6 and PLT2 mice were similarly increased after Poly I:C immunotherapy, and expressed high levels of CD40 and CD86. CD8+ T cells in the tumor-dLN and tumor of both WT and PLT2 mice were also increased after Poly I:C immunotherapy, and were able to secrete increased IFNγ upon in vitro restimulation. Surprisingly, tumor-specific CD8+ T cells in dLN were less abundant in PLT2 mice compared to C57BL/6, but showed a greater ability to proliferate even in the absence of cognate antigen. These data suggest that hyperuricaemia may affect the functionality of CD8+ T cells in vivo, leading to dysregulated T cell proliferation and impaired anti-tumor activity.
Highlights
Metabolic syndrome (MS) describes the metabolic dysfunction associated with obesity and increased risk of type 2 diabetes mellitus and cardiovascular diseases
We tested the impact of the point mutation in the gene encoding for hydroxyisourate hydrolase (HIU-H) on the efficacy of tumor immunotherapy in C57BL/6 wild-type (WT) and PLT2 mice challenged with B16-F1 melanoma
Tumor growth and survival were comparable for WT and PLT2 PBS-treated control mice but, where Poly I:C treatment delayed tumor growth and extended survival in WT mice, Poly I:C treatment had no effect in tumor-bearing PLT2 mice (Fig 1A and 1B)
Summary
Metabolic syndrome (MS) describes the metabolic dysfunction associated with obesity and increased risk of type 2 diabetes mellitus and cardiovascular diseases. The alarming increase in MS has become a major health concern internationally. These concerns arise from the life-threatening nature of the MS itself but are due to the negative impact it has on other diseases including cancer [1,2,3]. Hyperuricaemia impairs tumor immunotherapy that shows a strong link between MS and a number of different cancers in both men and women, ranging from colorectal [4, 5] through to prostate [6] and breast cancers [7, 8]. There is evidence of links between carcinogenesis and changes in glucose and/or lipid metabolism [10, 11], as well as chronic MS-related inflammation [12, 13]
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