Liver metastases license neutrophils throygh IL-1 to potentiate cancer progression
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ABSTRACT:
PROVIDER: PRJNA1228252 | ENA |
REPOSITORIES: ENA
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Project description:Liver metastases are associated with poor cancer outcomes in many solid malignancies, but the factors influencing the trajectory of patients with liver metastases are poorly defined. It is known that liver metastases suppress systemic antitumor immunity; however, the underlying mechanisms remain incompletely described. We report that liver metastases promote disease progression in patients and preclinical models. Patients with liver metastases progress rapidly, regardless of primary tumor type. In multiple murine models, we find that liver metastases potentiate neutrophil migration and activity. Neutrophils licensed by liver metastasis augment metastatic colonization in an IL-1 dependent fashion. Thus, liver metastasis rewires systemic immunity to promote cancer progression. This work has implications for novel treatment strategies to address the poor clinical outcomes associated with liver metastasis.
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Project description:Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer remains largely unknown, especially in refractory tumors including bone metastases. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. DKK1 induces the immature-like functional state in neutrophils, which exert robust immunosuppressive capabilities to inhibit anti-tumor response of CD8+ T cells. Mechanistically, driven by the DKK1-CKAP4-STAT6 signaling, Chil3 expression is identified and required for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, using multiple syngeneic and human immune system (HIS) mouse models, we found that DKK1 blockade efficiently allows neutrophil maturation to improve the immune microenvironment, controls tumor progression, and enhances ICB therapy response in bone metastases. Thus, our findings uncover an essential role for immature neutrophils in cancer, especially in bone metastases, and propose a potential strategy modulating neutrophils to improve cancer immunotherapy.
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