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

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.

SUBMITTER: Chen X 

PROVIDER: S-EPMC5384347 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature