Host dysbiosis negatively impacts IL-9-producing T-cell differentiation and antitumour immunity
Rafael Ribeiro Almeida, Raquel de Souza Vieira, Ângela Castoldi, Fernanda Fernandes Terra, Amanda Campelo Lima de Melo, Maria Cecília Campos Canesso, Luísa Lemos, Marcella Cipelli, Nisha Rana, Meire Ioshie Hiyane, Erika L. Pearce, Flaviano S. Martins, Ana Maria Caetano Faria, Niels Olsen Saraiva Câmara
Abstract
BACKGROUND: Host-microbiota interactions shape T-cell differentiation and promote tumour immunity. Although IL-9-producing T cells have been described as potent antitumour effectors, their role in microbiota-mediated tumour control remains unclear. METHODS: We analysed the impact of the intestinal microbiota on the differentiation of colonic lamina propria IL-9-producing T cells in germ-free and dysbiotic mice. Systemic effects of the intestinal microbiota on IL-9-producing T cells and the antitumour role of IL-9 were analysed in a model of melanoma-challenged dysbiotic mice. RESULTS: We show that germ-free mice have lower frequency of colonic lamina propria IL-9-producing T cells when compared with conventional mice, and that intestinal microbiota reconstitution restores cell frequencies. Long-term antibiotic treatment promotes host dysbiosis, diminishes intestinal IL-4 and TGF-β gene expression, decreases the frequency of colonic lamina propria IL-9-producing T cells, increases the susceptibility to tumour development and reduces the frequency of IL-9-producing T cells in the tumour microenvironment. Faecal transplant restores intestinal microbiota diversity, and the frequency of IL-9-producing T cells in the lungs of dysbiotic animals, restraining tumour burden. Finally, recombinant IL-9 injection enhances tumour control in dysbiotic mice. CONCLUSIONS: Host-microbiota interactions are required for adequate differentiation and antitumour function of IL-9-producing T cells.