This study reveals a significant correlation between ECM3 gene expression profiles and reduced PD-1 expression on Treg cells, and elucidates the molecular mechanism whereby SPARC induces IL-23 release to suppress PD-1 expression. Importantly, blocking IL-23 restores PD-1 expression on Treg cells and activates effector T cells, providing novel strategic directions for immunotherapy in high-grade breast cancer.
Literature Overview
This article 'ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs' published in the Journal of Experimental & Clinical Cancer Research reviews the relationship between tumor microenvironment (TME) and immune regulation in high-grade breast cancer (HGBC), particularly focusing on the association between ECM3 gene expression signatures and PD-1 downregulation on Treg cells. The study further demonstrates that SPARC promotes immune suppression by enhancing IL-23 release and suppressing SATB1 expression, leading to reduced PD-1 levels and increased Treg cell immunosuppressive activity.
Background Knowledge
High-grade breast cancer (HGBC) represents an aggressive subtype with poor prognosis and limited response to current immune checkpoint blockade (ICB) therapies. ECM3 expression signatures are closely linked to epithelial-mesenchymal transition (EMT) and immunosuppressive tumor microenvironment. Treg cells serve as critical mediators of immune suppression, with their functional activity directly influenced by PD-1 expression levels. SPARC, a key ECM3 component, has been established to promote tumor progression and immune suppression across multiple cancer models. However, the precise regulatory mechanisms through which SPARC modulates IL-23 and SATB1 to affect Treg PD-1 expression remain incompletely understood. This study systematically investigates the expansion mechanism of PD-1⁻ Treg cells in ECM3⁺ tumors using gene expression profiling, flow cytometry, immunohistochemistry, functional inhibition assays, and explores the therapeutic potential of targeting IL-23 or SATB1.
Research Methods and Experiments
The research team analyzed phenotypic changes of Treg cells in peripheral blood mononuclear cells (PBMC) from HGBC patients using flow cytometry, with in vivo validation conducted in mouse tumor models (4T1cl5, 4T1SPARC, SN25A). Comprehensive analyses of SPARC, IL-23, SATB1, and PD-1 expression and functional relationships were performed through gene knockout, overexpression, flow cytometry cell sorting, qPCR, Western blot, immunofluorescence, and in vitro suppression assays. Additionally, single-cell RNA-seq dataset (GSE110686) was employed to examine IL-23R and PDCD1 expression in T cells, confirming the specific action of IL-23 on Treg cells.
Key Conclusions and Perspectives
Research Significance and Prospects
This work identifies novel regulatory mechanisms between ECM3 and immune checkpoints, providing mechanistic insights into immunotherapy resistance in HGBC patients. Targeting IL-23 or SATB1 emerges as promising therapeutic strategies. Future studies should evaluate combination therapies involving IL-23 antibodies or SATB1 inhibitors with chemotherapy and other immune checkpoint inhibitors, while clinical validation is required to establish ECM3 as a reliable biomarker for PD-1/PD-L1 treatment resistance.
Conclusion
This study systematically demonstrates that ECM3 gene expression signatures suppress Treg cell PD-1 expression through the SPARC/IL-23/SATB1 axis in breast cancer, enhancing immunosuppressive function and causing T cell exclusion and resistance to immunotherapy. This mechanism provides new molecular targets for developing immune therapeutic strategies in high-grade breast cancer, while highlighting ECM3 as a potential biomarker for identifying patients with poor response to PD-1/PD-L1 inhibitors. Future preclinical investigations and translational medicine analyses combining IL-23 or SATB1-targeted therapies will advance personalized immunotherapy development.
