Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3(+) regulatory T cells in murine colon cancer.

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Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3(+) regulatory T cells in murine colon cancer.

Oncoimmunology. 2017;6(3):e1290034

Authors: Chen X, Takemoto Y, Deng H, Middelhoff M, Friedman RA, Chu TH, Churchill MJ, Ma Y, Nagar KK, Tailor YH, Mukherjee S, Wang TC

Abstract
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-LSL-tdTomato 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.

PMID: 28405523 [PubMed - in process]

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