Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel.
Department of Pathology, Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel.
J Leukoc Biol. 2024 Jul 25;116(2):424-435. doi: 10.1093/jleuko/qiae063.
Eosinophils have been mainly studied in allergic diseases and parasitic infections. Nonetheless, eosinophils accumulate in a variety of solid tumors, including colorectal cancer, where their presence is associated with improved prognosis. Eosinophils can promote antitumor immunity through various mechanisms, including direct cytotoxicity toward tumor cells and promoting T-cell activation. However, the mechanisms by which tumor cells regulate eosinophil activities are largely unknown. Herein, we characterized the potential interactions between eosinophils and colorectal cancer cells using an unbiased transcriptomic and proteomic analyses approach. Human eosinophils were stimulated with colorectal cancer cell conditioned media, containing tumor cell secreted factors from multiple cancer cell lines. RNA sequencing analysis identified a "core" signature consisting of 101 genes that characterize a baseline transcriptional program for the response of human eosinophils to colorectal cancer cells. Among these, the increased expression of IL-3Rα and its βc chain was identified and validated at the protein level. Secreted factors from tumor cells potentiated IL-3-induced expression of the adhesion molecule CD11a in eosinophils. Combining proteomics analysis of tumor cell secreted factors with RNA sequencing revealed potential ligand-receptor pairs between tumor cells and eosinophils and the potential involvement of the adhesion molecule CD18 and F2RL3/PAR4. Subsequent functional analyses demonstrated that F2RL3/PAR4 suppresses eosinophil migration in response tumor cell secreted factors. These findings add to the growing body of evidence that eosinophils are conditioned by their local microenvironment. Identifying mechanisms by which eosinophils interact with tumor cells could lead to the development of new immunotherapies for colorectal cancer and other solid tumors.
嗜酸性粒细胞主要在过敏疾病和寄生虫感染中进行研究。然而，嗜酸性粒细胞在多种实体肿瘤中积累，包括结直肠癌，其存在与改善预后相关。嗜酸性粒细胞可以通过多种机制促进抗肿瘤免疫，包括对肿瘤细胞的直接细胞毒性和促进 T 细胞激活。然而，肿瘤细胞调节嗜酸性粒细胞活性的机制在很大程度上尚不清楚。在此，我们使用无偏倚的转录组和蛋白质组分析方法来表征嗜酸性粒细胞与结直肠癌细胞之间的潜在相互作用。用含有来自多种癌细胞系的肿瘤细胞分泌因子的结直肠癌细胞条件培养基刺激人嗜酸性粒细胞。RNA 测序分析确定了一个由 101 个基因组成的“核心”特征，该特征描述了人嗜酸性粒细胞对结直肠癌细胞反应的基线转录程序。在这些基因中，鉴定并验证了白细胞介素 3 受体 α（IL-3Rα）及其βc 链的表达增加。肿瘤细胞分泌的因子增强了嗜酸性粒细胞中白细胞介素 3 诱导的黏附分子 CD11a 的表达。结合肿瘤细胞分泌因子的蛋白质组分析和 RNA 测序揭示了肿瘤细胞和嗜酸性粒细胞之间潜在的配体-受体对，以及黏附分子 CD18 和 F2RL3/PAR4 的潜在参与。随后的功能分析表明，F2RL3/PAR4 抑制嗜酸性粒细胞对肿瘤细胞分泌因子的迁移。这些发现增加了越来越多的证据表明，嗜酸性粒细胞受其局部微环境调节。鉴定嗜酸性粒细胞与肿瘤细胞相互作用的机制可能导致开发用于结直肠癌和其他实体瘤的新免疫疗法。
