Shiri Ahmad Mustafa, Fard-Aghaie Mohammad, Bedke Tanja, Papazoglou Eleftherios D, Sabihi Morsal, Zazara Dmitra E, Zhang Siwen, Lücke Jöran, Seeger Philipp, Evers Maximilian, Hackert Thilo, Oldhafer Karl J, Gondolesi Gabriel E, Huber Samuel, Giannou Anastasios D
Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Sci Rep. 2024 Dec 16;14(1):30483. doi: 10.1038/s41598-024-80437-8.
The lung is one of the most frequently metastasized organs from various cancer entities, especially colorectal cancer (CRC). The occurrence of lung metastasis correlates with worse prognosis in CRC patients. Here, we aimed to investigate the role of IL-10 in lung metastasis development and identify the cellular source and target cells of IL-10 during lung metastatic establishment. To induce lung metastasis in mice, we injected MC38 murine colon cancer cells intravenously. Mice with Il10-deficiency were used to test the role of IL-10. The lung metastatic burden was assessed both macroscopically and histologically. IL-10- and Foxp3-reporter mice were employed to identify the cellular source and target cells of IL-10 in lung metastasis using flow cytometry. These findings were further confirmed using mice with cell-specific deletion of Il10- and IL-10 receptor (Il10ra). Interestingly, Il10 ablation led to reduced lung metastasis formation, suggesting a pathogenic role of IL-10 in lung metastasis. Moreover, using reporter mice, we identified Foxp3 + regulatory T cells (Tregs) as the predominant cellular source of IL-10 in lung metastasis. Accordingly, Foxp3 + Treg-specific deletion of Il10 resulted in decreased lung metastasis formation. In terms of target cells, myeloid cells and Foxp3 + Tregs expressed high IL-10Ra levels. Indeed, IL-10 signaling blockade in these two immune cell populations resulted in reduced lung metastatic burden. In conclusion, Foxp3 + Treg-derived IL-10 was found to act on Foxp3 + Tregs and myeloid cells, thereby promoting lung metastasis formation. These findings provide insights into lung metastasis-related immunity and establish the groundwork for optimizing metastasis-targeting immunotherapies through targeting of IL-10 as a novel therapeutic strategy.
肺是各种癌症实体最常发生转移的器官之一，尤其是结直肠癌（CRC）。肺转移的发生与CRC患者较差的预后相关。在此，我们旨在研究白细胞介素10（IL-10）在肺转移发展中的作用，并确定肺转移形成过程中IL-10的细胞来源和靶细胞。为了在小鼠中诱导肺转移，我们静脉注射了MC38小鼠结肠癌细胞。使用Il10基因缺陷的小鼠来测试IL-10的作用。通过宏观和组织学评估肺转移负担。使用IL-10和叉头框蛋白3（Foxp3）报告基因小鼠，通过流式细胞术确定肺转移中IL-10的细胞来源和靶细胞。使用Il10和IL-10受体（Il10ra）细胞特异性缺失的小鼠进一步证实了这些发现。有趣的是，Il10基因敲除导致肺转移形成减少，表明IL-10在肺转移中起致病作用。此外，使用报告基因小鼠，我们确定Foxp3 +调节性T细胞（Tregs）是肺转移中IL-10的主要细胞来源。因此，Foxp3 + Treg特异性缺失Il10导致肺转移形成减少。就靶细胞而言，髓样细胞和Foxp3 + Tregs表达高水平的IL-10Ra。事实上，这两种免疫细胞群体中的IL-10信号阻断导致肺转移负担减轻。总之，发现Foxp3 + Treg衍生的IL-10作用于Foxp3 + Tregs和髓样细胞，从而促进肺转移形成。这些发现为肺转移相关免疫提供了见解，并为通过将IL-10作为一种新的治疗策略进行靶向来优化转移靶向免疫疗法奠定了基础。
