The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis.
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 MinApc+/-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.
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
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E
Thiele Orberg
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
H
H
Fan
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
A J
AJ
Tam
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
C M
CM
Dejea
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
C E
CE
Destefano Shields
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
S
S
Wu
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
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L
Chung
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
B B
BB
Finard
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
X
X
Wu
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
P
P
Fathi
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
S
S
Ganguly
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
J
J
Fu
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
D M
DM
Pardoll
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
C L
CL
Sears
Oncology Department, Johns Hopkins University, Baltimore, Maryland, USA.|Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
F
F
Housseau
D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000276:immunology; D001442:Bacteroides Infections / Q000276:immunology*; D001441:Bacteroides fragilis / Q000276:immunology*; D063646:Carcinogenesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology*; D017491:Genes, APC; D006801:Humans; D007108:Immune Tolerance; D020381:Interleukin-17 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D059467:Transcriptome
D001427:Bacterial Toxins; D020381:Interleukin-17; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C405031:Bacteroides fragilis toxin; D008666:Metalloendopeptidases; C544448:Arg1 protein, mouse; D001119:Arginase