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Neutrophil-specific targeting of STAT3 impairs tumor progression via the expansion of cytotoxic CD8+ T cells

ABSTRACT: Neutrophils have emerged as key players in tumor progression, often associated with poor prognosis. Despite the ongoing efforts to target neutrophil functions in cancer, therapeutic success has been limited. In this study, we addressed the possibility of blocking STAT3 signaling in neutrophils as targeted therapeutic intervention in cancer. Conditional deletion of Stat3 in neutrophil-specific manner (Ly6GcreStat3fl/fl mice) significantly impaired tumor growth and metastasis in mice. Neutrophils isolated from these mice exhibited strong antitumoral phenotype, with increased MHCII, CD80/86 and ICAM-1 expression. Immune profiling of tumors and tumor-draining lymph nodes revealed a significant enrichment of CD8+ T cells (granzymeBhi, perforinhi and IFN-γhi) with strong cytotoxic activity. To further translate these findings to human settings, we blocked STAT3 signaling in patient neutrophils using a small molecule inhibitor LLL12 and assessed their effects on patient-derived cancer explants. In agreement with in vivo mouse data, we observed the expansion and activation of cytotoxic CD8+ T cells in such explants. To test the therapeutic applicability of STAT3 targeting, we utilized myeloid cell-selective STAT3 siRNA (CpG-STAT3ASO) to target neutrophils in vivo in tumor-bearing mice. Consistent with previous results, neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in tumors and tumor-draining lymph nodes of treated mice. These findings highlight STAT3 signaling as a deleterious pathway supporting protumoral activity of neutrophils and suggest neutrophil-targeted STAT3 inhibition as a promising opportunity for cancer immunotherapy, providing novel insights in targeted therapeutic avenues.

ORGANISM(S): Mus musculus

PROVIDER: GSE300511 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens whose siderophores would normally be chelated by 24p3. Specific granule deficiency (SGD) is a rare congenital disorder characterized by complete absence of proteins in secondary granules. Neutrophils from SGD patients, who are prone to bacterial infections, lack normal functions but the potential role of 24p3 in neutrophil dysfunction in SGD is not known. Here we show that neutrophils from 24p3-deficient mice are defective in many neutrophil functions. Specifically, neutrophils in 24p3-deficient mice do not extravasate to sites of infection and are defective for chemotaxis. A transcriptome analysis revealed that genes that control cytoskeletal reorganization are selectively suppressed in 24p3-deficient neutrophils. Additionally, small regulatory RNAs (miRNAs) that control upstream regulators of cytoskeletal proteins are also increased in 24p3-deficient neutrophils. Further, 24p3-deficient neutrophils failed to phagocytose bacteria, which may account for the enhanced sensitivity of 24p3-deficient mice to both intracellular (Listeria monocytogenes) and extracellular (Candida albicans, Staphylococcus aureus) pathogens. Interestingly, Listeria does not secrete siderophores and additionally, the siderophore secreted by Candida is not sequestered by 24p3. Therefore, the heightened sensitivity of 24p3-deficient mice to these pathogens is not due to sequestration of siderophores limiting iron availability, but is a consequence of impaired neutrophil function. Key words: Lipocalin, 24p3, neutrophils, cell motility, chemotaxis, MIRNA-362-3p To address the role of lipocalin 2 in regulating miRNA expression profiling in neutrophils derived from mouse bone marrow, we performed microarray analysis of miRNAs in wild type (N=2) and lcn2 knockout (N=2) neutrophils.

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Neutrophil-specific targeting of STAT3 impairs tumor progression via the expansion of cytotoxic CD8+ T cells

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