Macrophage-derived is associated with reduced CD8 T cell infiltration and poorer outcomes in cancer.
Elevated SPP1 levels in tumor-associated macrophages are linked to decreased CD8 T cell presence in tumors.
Genetic deletion of SPP1 in macrophages led to increased CD8 T cell populations and improved tumor suppression.
SPP1 deficiency in macrophages is associated with elevated mitochondrial reactive oxygen species (ROS) production.
Accumulation of cytosolic double-stranded DNA fragments activates the , enhancing immune response mechanisms.
Upregulation of chemokines CXCL9 and CXCL10 occurs in response to SPP1 deletion, promoting CD8 T cell recruitment.
Simplified
BACKGROUND: Elevated levels of SPP1tumor-associated macrophages (TAMs) are associated with reduced CD8T cell infiltration and poorer prognosis in cancer patients, but direct evidence demonstrating a causal role for SPP1TAMs in excluding CD8T cells is still missing. The precise mechanisms by which -activated signaling pathways and macrophage-derived factors regulate CD8T cell trafficking remain poorly understood. + + + + +
METHODS: We established multiple tumor mouse models to study the function of macrophage SPP1 in the tumor environment, especially its role in the relationship between macrophages and CD8 T cells. We combined the single-cell (sc) RNA sequencing data of clinical tumor samples and tumor tissues from Spp1mice to identify the differences in SPP1-related genes and found that SPP1 could regulate the expression of CXCL9 and CXCL10 in macrophages. Through Western blotting, immunofluorescence staining, and flow cytometry analyses, we elucidated the mechanistic basis by which macrophage-specific SPP1 deficiency suppressed tumorigenesis. fl/fl-Lyz2-Cre
RESULTS: This study demonstrated that macrophage-derived SPP1 played a crucial role in suppressing CD8 T cell infiltration, promoting tumor progression, and diminishing the effectiveness of immune checkpoint inhibitor (ICI) therapy. Sc-RNA sequencing analysis revealed a marked increase in CD8 T cell populations within tumor tissues of Spp1mice. Furthermore, a negative correlation was observed between CD8 T cells and SPP1 macrophages in human colorectal cancer specimens. Genetic deletion of SPP1 in macrophages markedly enhanced tumor growth suppression in a manner dependent on CD8 T cell-mediated immunity. Mechanistically, SPP1 deficiency in macrophages led to elevated mitochondrial reactive oxygen species (ROS) production, resulting in the accumulation of cytosolic double-stranded DNA (dsDNA) fragments. This accumulated dsDNA activated the , leading to subsequent STAT1 phosphorylation. The enhanced STAT1 activity upregulated the expression of chemokines CXCL9 and CXCL10, thereby facilitating CD8 T cell recruitment into the tumor microenvironment. fl/fl-Lyz2-Cre
CONCLUSIONS: Deletion of SPP1 in TAMs upregulates CXCL9/10 production by activating the ROS-DNA fragment/cGAS-STING/STAT1 pathway, thereby enhancing CD8 T cell infiltration, inhibiting tumor progression, and improving ICI treatment outcomes in tumors.
Key numbers
2.3×
Increase in CD8 T Cell Infiltration
CD8 T cell populations in Spp1mice vs. control Spp1mice.
50%
Tumor Volume Reduction
Tumor volume in Spp1mice compared to control Spp1mice.
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