Spatial profiling reveals unique immune microenvironment in premenopausal triple-negative breast cancer associated with therapy response

Document Type

Article

Publication Title

Journal of Translational Medicine

Abstract

Background: Triple-negative breast cancer (TNBC) lacks targeted therapies, leading to a poor prognosis. Younger patients with TNBC often present with aggressive disease and exhibit distinct tumor microenvironments (TME). We performed spatial profiling to understand the influence of menopausal status on the immune environment, tumor progression, and therapy response. Methods: Eleven treatment-naive TNBC tumors were examined in epithelial and non-epithelial areas using digital spatial profiling to identify differentially expressed markers and pathways. Deconvolution methods were employed to identify immune cell subtypes, and the protein expression of T and B cells was confirmed. The prognostic utility of the identified genes and pathways was validated using the METABRIC and SCAN-B datasets. The expression of target genes was analyzed in the I-SPY 2 trial data to understand their influence on the response to specific therapies. Results: Premenopausal tumors formed a distinct cluster characterized by the upregulation of cell activation and antigen presentation pathways. In contrast, T cell checkpoint, cancer antigen, and PI3K-AKT pathways were downregulated. External datasets validated these findings, showing a lower hazard and better prognosis for genes upregulated in premenopausal tumors. An enrichment of CD8 + T cells, endothelial cells, and monocytes was observed, along with increased intratumoral protein expression of CD8, CD4, and CD20. Premenopausal tumors demonstrated better responses to PARP and HSP90 inhibitors but showed lower sensitivity to Pembrolizumab and PI3K-AKT inhibitors compared to postmenopausal tumors in the I-SPY 2 trial data. Conclusion: Our study underscores the importance of menopausal status in shaping the TME within TNBC, revealing distinct immune landscapes and therapy responses. These findings highlight the need for larger prospective studies to validate differential treatment strategies in younger patients.

DOI

10.1186/s12967-025-06786-8

Publication Date

12-1-2025

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