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

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

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