Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer

Zina Dubeykovskaya; Yiling Si; Xiaowei Chen; Daniel L Worthley; Bernhard W Renz; Aleksandra M Urbanska; Yoku Hayakawa; Ting Xu; C Benedikt Westphalen; Alexander Dubeykovskiy; Duan Chen; Richard A Friedman; Samuel Asfaha; Karan Nagar; Yagnesh Tailor; Sureshkumar Muthupalani; James G Fox; Jan Kitajewski; Timothy C Wang

doi:10.1038/ncomms10517

Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer

Nat Commun. 2016 Feb 4:7:10517. doi: 10.1038/ncomms10517.

Authors

Zina Dubeykovskaya¹, Yiling Si¹, Xiaowei Chen¹, Daniel L Worthley¹, Bernhard W Renz^{1

2}, Aleksandra M Urbanska¹, Yoku Hayakawa¹, Ting Xu¹, C Benedikt Westphalen¹, Alexander Dubeykovskiy¹, Duan Chen³, Richard A Friedman⁴, Samuel Asfaha¹, Karan Nagar¹, Yagnesh Tailor¹, Sureshkumar Muthupalani⁵, James G Fox⁵, Jan Kitajewski⁶, Timothy C Wang¹

Affiliations

¹ Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
² Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany.
³ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Pb 8905, N-7491 Trondheim, Norway.
⁴ Department of Biomedical Informatics, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
⁵ Department of Biological Engineering, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
⁶ Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.

Abstract

CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) expand in the spleen during cancer and promote progression through suppression of cytotoxic T cells. An anti-inflammatory reflex arc involving the vagus nerve and memory T cells is necessary for resolution of acute inflammation. Failure of this neural circuit could promote procarcinogenic inflammation and altered tumour immunity. Here we show that splenic TFF2, a secreted anti-inflammatory peptide, is released by vagally modulated memory T cells to suppress the expansion of MDSCs through CXCR4. Splenic denervation interrupts the anti-inflammatory neural arc, resulting in the expansion of MDSCs and colorectal cancer. Deletion of Tff2 recapitulates splenic denervation to promote carcinogenesis. Colorectal carcinogenesis could be suppressed through transgenic overexpression of TFF2, adenoviral transfer of TFF2 or transplantation of TFF2-expressing bone marrow. TFF2 is important to the anti-inflammatory reflex arc and plays an essential role in arresting MDSC proliferation. TFF2 offers a potential approach to prevent and to treat cancer.

MeSH terms

Adoptive Transfer
Animals
Blotting, Western
Bone Marrow Transplantation
Cell Proliferation / genetics*
Colitis / genetics*
Colitis / immunology
Colon / metabolism
Colon / pathology
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / immunology
Cytokines / immunology
Denervation
Disease Progression
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Immunohistochemistry
Inflammation
Mice
Mice, Inbred C57BL
Mice, Knockout
Mucins / genetics*
Mucins / immunology
Mucins / metabolism
Muscle Proteins / genetics*
Muscle Proteins / immunology
Muscle Proteins / metabolism
Myeloid Cells / immunology*
Neoplasms / genetics
Neoplasms / immunology
Peptides / genetics*
Peptides / immunology
Peptides / metabolism
Permeability
Receptors, CXCR4 / immunology*
Reverse Transcriptase Polymerase Chain Reaction
Spleen / immunology*
Spleen / innervation
T-Lymphocyte Subsets / immunology
T-Lymphocytes, Cytotoxic / immunology*
Trefoil Factor-2
Vagotomy, Truncal
Vagus Nerve Stimulation
Vagus Nerve*

Substances

CXCR4 protein, mouse
Cytokines
Mucins
Muscle Proteins
Peptides
Receptors, CXCR4
TFF2 protein, mouse
Trefoil Factor-2

Abstract

MeSH terms

Substances

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