The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis.

Thiele Orberg E, Fan H, Tam AJ, Dejea CM, Destefano Shields CE, Wu S, Chung L, Finard BB, Wu X, Fathi P, Ganguly S, Fu J, Pardoll DM, Sears CL, Housseau F
Mucosal Immunol. 2017 10 (2): 421-433

PMID: 27301879 · PMCID: PMC5159334 · DOI:10.1038/mi.2016.53

Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of interleukin-17 (IL-17)-dependent colon tumorigenesis in Min mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling. Cell-sorted immature myeloid cells were functionally assayed for inhibition of T-cell proliferation and inducible nitric oxide synthase expression to delineate MDSC populations. A comparison of ETBF infection with that of other oncogenic bacteria (Fusobacterium nucleatum or pksEscherichia coli) revealed a specific, ETBF-associated colonic immune infiltrate. ETBF-triggered colon tumorigenesis is associated with an IL-17-driven myeloid signature characterized by subversion of steady-state myelopoiesis in favor of the generation of protumoral monocytic-MDSCs (MO-MDSCs). Combined action of the B. fragilis enterotoxin BFT and IL-17 on colonic epithelial cells promoted the differentiation of MO-MDSCs, which selectively upregulated Arg1 and Nos2, produced NO, and suppressed T-cell proliferation. Evidence of a pathogenic inflammatory signature in humans colonized with ETBF may allow for the identification of populations at risk for developing colon cancer.

MeSH Terms (25)

Animals Arginase Bacterial Toxins Bacteroides fragilis Bacteroides Infections Carcinogenesis Cell Differentiation Cell Proliferation Cells, Cultured Colon Colorectal Neoplasms Disease Models, Animal Epithelial Cells Genes, APC Humans Immune Tolerance Interleukin-17 Metalloendopeptidases Mice Mice, Inbred C57BL Mice, Mutant Strains Myeloid-Derived Suppressor Cells Nitric Oxide Synthase Type II T-Lymphocytes Transcriptome

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