Mast Cell–Dependent CD8+ T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in ApcMin/+ Mice

Abstract

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^Min/+)</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^-/-Apc^Min/+ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell-deficient ACKR2^-/-SA^-/-Apc^Min/+ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth. Mast cells from ACKR2^-/- mice showed elevated CCR2 and CCR5 expression and were also efficient in antigen presentation and activation of CD8⁺ T cells. Mast cell-derived leukotriene B₄ (LTB₄) was found to be required for CD8⁺ T lymphocyte recruitment, as mice lacking the LTB₄ receptor (ACKR2^-/-BLT1^-/-Apc^Min/+) were highly susceptible to intestinal tumor-induced mortality. Taken together, these data demonstrate that chemokine-mediated recruitment of mast cells is essential for initiating LTB₄/BLT1-regulated CD8⁺ 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>.