IL-36β promotes anti-tumor effects in CD8+ T cells by downregulating micro-RNA let-7c-5p

Abstract

BACKGROUND: The anti-tumor effect of interleukin (IL)-36β-mediated activation of CD8(+) T cells has been reported, but the molecular mechanism is largely undefined. METHODS: The levels of IL-36β in pancreatic cancer were examined by quantitative real-time PCR (qRT-PCR) and immunohistochemical staining. Cytology and animal experiments were performed to study the effects of IL-36β on the growth of pancreatic cancer cells. We then examined the changes of CD8(+) T cells and natural killer (NK) cells in the tumor by flow cytometry. The microRNA expression profiles were determined by microarray analysis. RESULTS: The results revealed decreased levels of IL-36β in pancreatic cancer tissues. In addition, IL-36β inhibited tumor growth and promoted CD8(+) T and NK cell proliferation in the tumor microenvironment (TME). Moreover, IL-36β stimulated CD8(+) T cells to synthesize high amounts of interferon-gamma (IFN-γ) and IL-2. Microarray analysis showed that IL-36β administration to human and mouse CD8(+) T cells consistently downregulated the miRNA, let-7c-5p. Downregulation of let-7c-5p resulted in IFN-γ and IL-2 upregulation in CD8(+) T cells, whereas its upregulation had the opposite effect. Further experiments demonstrated that IL-36β downregulated IFN-γ in let-7c-5p(+) CD8(+) T cells. CONCLUSIONS: These findings suggest IL-36β promotes IFN-γ and IL-2 production in CD8(+) T cells, as well as anti-tumor effects in CD8(+) T cells by downregulating let-7c-5p.