期刊
ONCOIMMUNOLOGY
卷 6, 期 3, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2017.1290034
关键词
Colitis-associated colorectal cancer; Cxcl13/Cxcr5 axis; HDC+ myeloid cells; immunosuppression; regulatory T cells
资金
- NIH NIDDK [5R01DK048077, S10OD020056, S10RR027050]
- National Science Foundation of China [81300347]
- Mildred-Scheel-Stiftung Deutsche Krebshilfe, Germany [70111870]
The colorectal tumor microenvironment contains a diverse population of myeloid cells that are recruited and converted to immunosuppressive cells, thus facilitating tumor escape from immunoediting. We have identified a genetically and functionally distinct subset of dynamic bone marrow myeloid cells that are characterized by histidine decarboxylase (HDC) expression. Lineage tracing in Hdc-CreERT2; R26-LSLtdTomato mice revealed that in homeostasis, there is a strong bias by HDC+ myeloid cells toward the CD11b(+)Ly6G(hi) granulocytic lineage, which was accelerated during azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colonic carcinogenesis. More importantly, HDC+ myeloid cells strongly promoted colonic tumorigenesis, and colon tumor progression was profoundly suppressed by diphtheria toxin A (DTA)-mediated depletion of HDC+ granulocytic myeloid cells. In addition, tumor infiltration by Foxp3(+) regulatory T cells (Tregs) was markedly impaired following HDC+ myeloid cell depletion. We identified an HDC+ myeloid-derived Cxcl13/Cxcr5 axis that mediated Foxp3 expression and Treg proliferation. Ablation of HDC+ myeloid cells or disruption of the Cxcl13/Cxcr5 axis by gene knockdown impaired the production and recruitment of Tregs. Cxcl13 induction of Foxp3 expression in Tregs during tumorigenesis was associated with Stat3 phosphorylation. Overall, HDC+ granulocytic myeloid cells affect CD8(+) T cells directly and indirectly through the modulation of Tregs and thus appear to play key roles in suppressing tumoricidal immunity.
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