Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of IL-17-dependent colon tumorigenesis in Min mice.
In Chapters 2 and 3, we examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), 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 in order to delineate MDSC populations. A comparison of ETBF infection to that with other oncogenic bacteria (Fusobacterium nucleatum or pks+ E. 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 (MO)-MDSC. Combined action of the Bacteroides fragilis enterotoxin bft and IL-17 on colonic epithelial cells promoted the differentiation of MO-MDSC, 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.
In Chapter 4, we describe targeting MDSC with the aim of suppressing tumorigenesis. CXCR2, an inflammatory chemokine receptor expressed on neutrophils and granulocytic (PMN)-MDSC, was a strong modifier of ETBF-Min tumorigenesis. Inhibition of CXCR2, via genetic knockout or a synthetic peptide antagonist, pepducin, significantly decreased recruitment of PMN-MDSC to the colon, increased numbers of M1 macrophages and was anti-tumoral. Specific inhibitors of MDSC targeting CXC receptors are under development and may emerge as a novel arm in immunotherapy
