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

• Published in: Oncoimmunology Vol. 6; no. 3; p. e1290034
• Main Authors: Chen, Xiaowei, Takemoto, Yoshihiro, Deng, Huan, Middelhoff, Moritz, Friedman, Richard A., Chu, Timothy H., Churchill, Michael J., Ma, Yan, Nagar, Karan K., Tailor, Yagnesh H., Mukherjee, Siddhartha, Wang, Timothy C.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 04.03.2017; Taylor & Francis Group
• Subjects: Colitis-associated colorectal cancer; Cxcl13/Cxcr5 axis; HDC; hdc+ myeloid cells; immunosuppression; myeloid cells; Original Research; regulatory T cells; regulatory T cells; Cxcl13/Cxcr5 axis; immunosuppression; Colitis-associated colorectal cancer; HDC+ myeloid cells
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2017.1290034

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.