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.
Highlights
CD11b þ Gr-1 þ myeloid-derived suppressor cells (MDSCs) expand in the spleen during cancer and promote progression through suppression of cytotoxic T cells
Splenic Tff[2] expression is upregulated by the T-cell mitogen concanavalin A (Supplementary Fig. 1b), and we established that it was the splenic T cells, CD44hiCD62Llo memory T cells that expressed the highest levels of trefoil factor 2 (TFF2) (Fig. 1d and Supplementary Fig. 1c,d), as confirmed by quantitative reverse transcriptase–PCR, immunohistochemistry (Fig. 1f) and by Tff[2] quantitative PCR in sorted choline acetyltransferase-enhanced green fluorescent protein (ChAT-EGFP) cells (Fig. 1g)
TFF2 is induced in vivo by vagal stimulation and in vitro in CD4 þ T cell by adrenergic stimulation, and induction by DSS treatment was blocked by vagotomy
Summary
CD11b þ Gr-1 þ myeloid-derived suppressor cells (MDSCs) expand in the spleen during cancer and promote progression through suppression of cytotoxic T cells. An antiinflammatory 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. 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. In this report we show that TFF2 is expressed predominantly in splenic memory T cells, where it is regulated by the vagus nerve and suppresses colon carcinogenesis. We have extended the vagal efferent arc from suppression of acute inflammation to a role in coordinating procarcinogenic inflammation
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