Eosinophils Promote Colorectal Cancer through Expression of S100a8 and S100a9

Eosinophils are bone marrow-derived cells that have been largely implicated in Th2-associated diseases. However, recent data highlight key roles for eosinophils in non-classical Th2 settings (e.g metabolism, thermogenesis and tissue regeneration). Quite surprisingly despite the fact that the gastrointestinal (GI) tract is the largest eosinophil reservoir in the body, the roles of GI eosinophils have been largely understudied especially in chronic GI inflammation and subsequent tumorigenesis.

We now report that eosinophils are a bona-fide cellular compartment of the tumor microenvironment in colorectal cancer (CRC). Substantial eosinophilic infiltration was observed in three independent models of CRC, representing the genetically driven and inflammation-driven CRC models (i.e. Apc^min/+ model and AOM+DSS treatment, respectively), as well as in colonic orthotopic injection of a tumor epithelial cell line. Eosinophil recruitment was accompanied with decreased blood eosinophilia, suggesting active recruitment to the colon. AOM+DSS-treated eosinophil-deficient mice (ΔdblGATA mice) displayed decreased epithelial cell proliferation, decreased collagen deposition and decreased expression of matrix metaloproteinases and TNF-a. Consequently, tumor load was dramatically reduced in the colons of ΔdblGATA mice.

Microarray analysis of primary colonic eosinophils sorted at various stages of the tumorigenic process (naïve-, inflammatory-, tissue repair- and tumor associated-eosinophils) revealed dynamic regulation of colonic eosinophil mRNA expression during carcinogenesis. Interestingly, the pro-tumorigenic and clinically relevant genes s100a8 and s100a9 were strikingly and kinetically increased in colonic eosinophils (250-fold and 90-fold, respectively). Indeed, local and systemic expression of s100a8 and s100a9 were nearly diminished in AOM+DSS-treated ΔdblGATA mice, and re-constituted upon adoptive transfer of eosinophils into the colon.

These data establish a key and unforeseen pro-tumorigenic role for eosinophils in CRC. Furthermore, our results suggest that eosinophils can promote carcinogenesis via expression and secretion of s100a8 and s100a9.