Foxp3+Treg-derived IL-10 promotes colorectal cancer-derived lung metastasis

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.