Munitz, Ariel

Abstract Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow–derived cells that have been largely studied in the context of allergic diseases and parasite infections. Although tumor-associated eosinophilia has been described in various solid tumors including colorectal cancer, knowledge is still missing regarding eosinophil activities and even the basic question of whether the TME promotes eosinophil recruitment without additional manipulation (e.g., immunotherapy) is unclear. Herein, we report that eosinophils are recruited into developing tumors during induction of inflammation-induced colorectal cancer and in mice with the Apcmin/+ genotype, which develop spontaneous intestinal adenomas. Using adoptive transfer and cytokine neutralization experiments, we demonstrate that the TME supported prolonged eosinophil survival independent of IL5, an eosinophil survival cytokine. Tumor-infiltrating eosinophils consisted of degranulating eosinophils and were essential for tumor rejection independently of CD8+ T cells. Transcriptome and proteomic analysis revealed an IFNγ-linked signature for intratumoral eosinophils that was different from that of macrophages. Our data establish antitumorigenic roles for eosinophils in colorectal cancer. These findings may facilitate the development of pharmacologic treatments that could unleash antitumor responses by eosinophils, especially in colorectal cancer patients displaying eosinophilia.

Abstract Clinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2−/− and eotaxin-1/2−/− mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80+CD11b+ macrophages in DSS-induced epithelial injury and to CD68+ intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.