Eosinophils are an integral part of the tumor microenvironment exerting potent anti-tumorigenic functions
Reichman H.1, Rozenberg P.1, Itan M.1, Yarmolovski T.1, Brazowski E.2, Varol C.2, Gluck N.2, Pasmanik-Chor M.3, Qimron U.1, Bachelet I4, Karo-Atar D4, Munitz A.1,*
1Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel; 2Research Center for Digestive Disorders and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; 3Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 64239, Israel; 4Biotherapeutics Cluster, Augmanity Nano LTD, Nes Ziona, 74047 Israel
Over the past decade, the roles of various cells in the tumor microenvironment (TME) have been gradually elucidated; however, certain cells still remain in near-complete obscurity. Among these cells, our lack of knowledge regarding the role of eosinophils is highly surprising especially given the fact that tumor-associated eosinophilia has been first described more than 120 years ago, and that eosinophilia is frequently observed in many types of cancer. Thus, fundamental knowledge is missing regarding the roles and phenotypes 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 TME.
We report that eosinophils are a bona-fide cellular component of the TME in CRC. Extensive eosinophilic infiltration and degranulation was observed in three independent models of CRC [i.e. Apcmin/+ model, colitis-associated colorectal cancer (CAC) and orthotopic colonic injection of MC38 cells]. Consistently, analysis of “tumorigenic” and “uninvolved” biopsy sections of CRC patients revealed increased eosinophilic accumulation in the TME. Moreover, we show that a single intravenous injection of eosinophils into eosinophil deficient mice (ΔdblGATA mice) undergoing CAC or ΔdblGATA/Apcmin/+ mice resulted in substantial CCL11-mediated eosinophil recruitment to the TME, which fosters prolonged eosinophils survival via secretion of GM-CSF, IL-3 and IL-5.
Tumor associated eosinophils displayed potent anti-tumorigenic properties in vivo as well since tumor load (number and size) were dramatically increased in ΔdblGATA mice undergoing CAC and ΔdblGATA/Apcmin/+ mice. Increased tumor burden in ΔdblGATA mice was associated with decreased numbers of active caspase 3+ cells but no alterations in the levels of Ki-67+ and CD31+ cells. Consistently, eosinophils induced colorectal cancer cell death in vitro. Furthermore, the anti-tumorigenic effects of eosinophils in vivo were independent of changes in CD8+ T cells or MDSCs and were likely mediated by direct eosinophil-mediated cytotoxicity. Tumor-associated eosinophils upregulated multiple ITIM-bearing inhibitory receptors, which regulated their cytotoxic activity in vitro.
Our data establish key anti-tumorigenic roles for eosinophils in CRC and that their cytotoxic activities are regulated by ITIM-bearing inhibitory receptors. These findings may facilitate the development of new pharmacological treatments unleashing robust anti-tumor responses by eosinophils and will hopefully lead to the development of innovative eosinophil-oriented “checkpoint inhibitors”.