18 Eosinophils are an integral part of the tumour microenvironment in colorectal cancer exerting potent anti-tumorigenic activities

Introduction Tumor-associated eosinophilia has been first described more than 120 years ago, and is frequently observed in many types of cancer. Yet, fundamental knowledge is missing regarding the roles of tumor-associated eosinophils. Since gastrointestinal (GI) tract is the largest eosinophil reservoir in the body and a main organ for eosinophil-mediated diseases, we focused our studies on colorectal cancer (CRC) as a model system to define the roles of eosinophils in the tumour microenvironment (TME). Material and methods Eosinophil infiltration and function were studied in two independent models of colorectal cancer (CRC), representing the genetically driven and inflammation-driven CRC models (i.e. Apc min/+ model and AOM+DSS treatment, respectively). Results and discussions We report that eosinophils are an integral part of the TME in CRC. Eosinophils are actively and specifically recruited to the TME in both models, where they undergo degranulation. Moreover, we show that a single intravenous injection of eosinophils into eosinophil deficient mice (ΔdblGATA mice) undergoing colitis-associated colorectal cancer (CAC) or ΔdblGATA/ Apc min/+ mice resulted in substantial recruitment of eosinophils to the TME, which fosters prolonged eosinophils survival likely via secretion of GM-CSF, IL-3 and IL-5. Eosinophil-deficient ΔdblGATA mice undergoing CAC displayed significantly decreased survival, which was associated with increased tumour number and size. Similarly, generation of ΔdblGATA/ Apc min/+ mice revealed significantly decreased survival, which was associated with increased tumour burden, thereby suggesting an anti-tumorigenic role for eosinophils. Importantly, the anti-tumorigenic effects of eosinophils were independent of changes in CD8 + T cells or MDSCs and were accompanied with a specific decrease in anti-active caspase 3 + cells. No changes were observed in the numbers of Ki-67 + or CD31 + cells. Thus, supporting eosinophil-mediated cytotoxicity in-vivo . Indeed, eosinophils were capable of killing CRC cell lines in vitro . Conclusion Our data establish key anti-tumorigenic roles for eosinophils in CRC. These findings may facilitate the development of new pharmacological treatments unleashing robust anti-tumour responses by eosinophils and will hopefully lead to the development of innovative eosinophil-oriented ‘checkpoint inhibitors’.