Extracellular Matrix Regulates PD-1 on Tregs via IL-23 contributing to immune suppression in Breast Cancer

ABSTRACT: Background. High-grade breast cancer (HGBC) is an aggressive disease with a poor prognosis, highlighting the urgent need for new treatment strategies. The tumor microenvironment (TME), especially the extracellular matrix (ECM), plays a crucial role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (ECM3) is present in approximately 35% of HGBC patients and is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcomes, and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs). Methods. We investigated the impact of the ECM on T-cell regulation in HGBC patients, focusing on the correlation between ECM3+ tumors and regulatory T cells (Tregs). Using mouse models, we explored the role of the matricellular protein SPARC, a key component of the ECM3 signature, in modulating PD-1 expression on Tregs. Mechanistic studies were performed to identify the signaling pathway involving SPARC, IL-23, and the transcription factor SATB1. Additionally, the effect of IL-23 blockade on Treg function was evaluated using monoclonal antibodies. Results. We found a significant correlation between highly suppressive PD-1-negative Tregs and ECM3+ tumors. In mouse models, SPARC downregulated PD-1 expression on Tregs by promoting IL-23 release, which induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs explained the targeted effect of IL-23. Blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells.Conclusions. These findings enhance our understanding of the immune-regulatory functions of the ECM and highlight potential therapeutic targets for treating high-grade breast cancers by modulating Treg activity and boosting immune responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE282777 | GEO | 2025/09/10

REPOSITORIES: GEO