Host dysbiosis negatively impacts IL-9-producing T-cell differentiation and antitumour immunity

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.

Bowel inflammation in cancer patients: the microbiome, antibiotics and interleukin-9

“…Inhibiting IL-9 ameliorated the inflammation and severity of inflammatory bowel disease. As for cancer diseases, this indicates, in light of the new data from Almeida et al, 17 that there could be a link to gut inflammation, which enforces anti-tumoural effects through barrier-breaching and bacterial product presence beyond the gut. It is an interesting hypothesis that comes from this: is there a beneficial inflammatory signature that is mediated by IL-9 and resembles a state of colitis?…”

“…It is an interesting hypothesis that comes from this: is there a beneficial inflammatory signature that is mediated by IL-9 and resembles a state of colitis? Almeida et al 17 found that the host microbiota enhances in vivo T-cell-derived secretion of IL-9, thereby limiting cancer outgrowth (see Fig. 1 ).…”

“…In light of these pressing questions, one aspect now has been addressed in the manuscript from Almeida et al 17 This elegant work now brought up interleukin-9 (IL-9) as an induced parameter by specific microbial communities. IL-9 is a well-known immunologically pleiotropic molecule.…”

New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries

“…Th 9 cells are a distinct subset of CD4 + T cells which differentiate under the influence of IL-4 and TGF-ß and secrete IL-9 ( 69 , 70 ) and play an important role in anti-tumor immunity ( 71 , 72 ). The gut microbiome can also influence Th 9 development, as GF mice and antibiotics treated SPF mice have decreased colonic expression of IL-4 and TGF-ß, thus reducing IL-9 secreting T cell population ( 73 ).…”

“…Almeida et al noticed that GF mice have decreased expression of IL-4 and TGF- ß , thereby reducing Th9 cells and leading to increased subcutaneous melanoma tumor growth. FMT from conventional mice into GF mice restores IL-9 production and decreases tumor growth ( 73 ). Another evidence for microbial modulation of Th 9 cells is seen in squamous cell carcinoma (SCC), where Miao et al found that Th 9 expanded on exposure to Staphylococcal enterotoxin B (ETB) along with SCC antigens and affected increased cancer cell apoptosis.…”