Data from Mast Cell–Dependent CD8<sup>+</sup> T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in Apc<sup>Min/+</sup> Mice

Abstract

<div>Abstract<p>The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the <i>adenomatous polyposis coli gene (Apc<sup>Min/+</sup>)</i> displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2<sup>–/–</sup>Apc<sup>Min/+</sup> tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell–deficient ACKR2<sup>–/–</sup>SA<sup>–/–</sup>Apc<sup>Min/+</sup> mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2<sup>–/–</sup> mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8<sup>+</sup> T cells. Mast cell–derived leukotriene B<sub>4</sub> (LTB<sub>4</sub>) was found to be required for CD8<sup>+</sup> T lymphocyte recruitment, as mice lacking the LTB<sub>4</sub> receptor (ACKR2<sup>–/–</sup>BLT1<sup>–/–</sup>Apc<sup>Min/+</sup>) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB<sub>4</sub>/BLT1-regulated CD8<sup>+</sup> T-cell homing and generation of effective antitumor immunity against intestinal tumors. We speculate that the pathway reported here underlies the positive prognostic significance of mast cells in selected human tumors. <i>Cancer Immunol Res; 6(3); 332–47. ©2018 AACR</i>.</p></div>