Format

Send to

Choose Destination
Oncoimmunology. 2017 Feb 10;6(3):e1290034. doi: 10.1080/2162402X.2017.1290034. eCollection 2017.

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

Author information

1
Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
2
Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; Department of Surgery and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.
3
Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
4
Department of Biomedical Informatics and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
5
Division of Hematology/Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.

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+Ly6Ghi 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.

KEYWORDS:

Colitis-associated colorectal cancer; Cxcl13/Cxcr5 axis; HDC+ myeloid cells; immunosuppression; regulatory T cells

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center