title: Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer.
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.
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Zina
authors: Z
authors: Dubeykovskaya
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Yiling
authors: Y
authors: Si
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Xiaowei
authors: X
authors: Chen
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Daniel L
authors: DL
authors: Worthley
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.|Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany.
authors: Bernhard W
authors: BW
authors: Renz
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Aleksandra M
authors: AM
authors: Urbanska
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Yoku
authors: Y
authors: Hayakawa
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Ting
authors: T
authors: Xu
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: C Benedikt
authors: CB
authors: Westphalen
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Alexander
authors: A
authors: Dubeykovskiy
authors: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Pb 8905, N-7491 Trondheim, Norway.
authors: Duan
authors: D
authors: Chen
authors: Department of Biomedical Informatics, Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
authors: Richard A
authors: RA
authors: Friedman
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Samuel
authors: S
authors: Asfaha
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Karan
authors: K
authors: Nagar
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Yagnesh
authors: Y
authors: Tailor
authors: Department of Biological Engineering, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Sureshkumar
authors: S
authors: Muthupalani
authors: Department of Biological Engineering, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: James G
authors: JG
authors: Fox
authors: Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Jan
authors: J
authors: Kitajewski
authors: Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
authors: Timothy C
authors: TC
authors: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation / Q000235:genetics*; D003092:Colitis / Q000235:genetics* / Q000276:immunology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003714:Denervation; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010539:Permeability; D019718:Receptors, CXCR4 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology* / Q000294:innervation; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000071164:Trefoil Factor-2; D015167:Vagotomy, Truncal; D014630:Vagus Nerve; D055536:Vagus Nerve Stimulation
chemical_list: C514936:CXCR4 protein, mouse; D016207:Cytokines; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D019718:Receptors, CXCR4; C481546:TFF2 protein, mouse; D000071164:Trefoil Factor-2