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

E. Thiele Orberg, H. Fan, A. J. Tam, C. M. Dejea, C. E. Destefano Shields, S. Wu, L. Chung, B. B. Finard, X. Wu, P. Fathi, S. Ganguly, J. Fu, D. M. Pardoll, C. L. Sears, F. Housseau

Research output: Contribution to journalArticlepeer-review

Abstract

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 Apc+/-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 pks + Escherichia 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.

Original languageEnglish (US)
Pages (from-to)421-433
Number of pages13
JournalMucosal Immunology
Volume10
Issue number2
DOIs
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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