title: 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+Ly6Ghigranulocytic 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.
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takemoto
authors.affiliation: 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.
authors.forename: Huan
authors.initials: H
authors.lastname: Deng
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Moritz
authors.initials: M
authors.lastname: Middelhoff
authors.affiliation: Department of Biomedical Informatics and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Chu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Churchill
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Karan K
authors.initials: KK
authors.lastname: Nagar
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Yagnesh H
authors.initials: YH
authors.lastname: Tailor
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
keywords: Colitis-associated colorectal cancer; Cxcl13/Cxcr5 axis; HDC+ myeloid cells; immunosuppression; regulatory T cells