Abstract PS2-11-29: Deciphering the tumor microenvironment related to immune regulation in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer, with the features of tumor microenvironment and the underlying molecular mechanisms of immune-regulation remaining largely elusive. This study aimed to explore the immune landscape of TNBC by assessing tumor-infiltrating lymphocytes (TILs) level, programmed cell death ligand 1 (PD-L1) expression, and the degree of TIL infiltration within the tumor. Methods: Utilizing the GeoMX Digital Spatial Profiler platform, we also performed spatially resolved transcriptomic profiling of tumor, immune, and stromal cells, focusing on the distinctions between immune-activated and immune-suppressed phenotypes. Results: Immune-activated phenotypes, characterized by high TILs, PD-L1 positivity, and close proximity between tumor cells and TILs, were found to correlate with the basal-like immune-activated subtype based on transcriptomic alterations derived solely from tumor cells. These phenotypes were also associated with the upregulation of known immune-related pathways. In contrast, immune-suppressed phenotypes were linked to pathways involved in tumor progression, such as epithelial-mesenchymal transition, TGF-beta signaling, and angiogenesis. Notably, our transcriptomic analysis suggests that tumor cells play a more dominant role than immune cells in shaping the immune phenotype, as indicated by the greater number of differentially expressed genes in tumor cells rather than immune cells. Stratifying patients based on TILs and PD-L1 status revealed that the TIL+PD-L1+ subtype exhibited the most favorable prognosis, a finding further supported by TIL+PD-L1+ signature with excellent survival outcomes in public gene datasets. Conversely, the TIL-PD-L1- subtype displayed characteristics of an "cold" tumor, potentially driven by desmoplastic changes within the tumor microenvironment. Interestingly, the TIL+PD-L1- subtype, despite a high TILs level, was associated with poorer prognosis, likely due to a higher proportion of myeloid cells, decreased activity of immune cells, and increased activation of the adipogenesis pathway across cell types. This finding underscores that in the TIL+PD-L1- subtype, immune cell activity remains low even when TILs infiltrate the intra-tumoral region, highlighting PD-L1 as a critical marker reflecting the immune system status in patients with high TILs. Conclusion: In summary, this study emphasizes the clinical significance of integrating TILs and PD-L1 expression as prognostic biomarkers in TNBC and underscores the central role of tumor cells in dictating immune phenotypes. Furthermore, our findings suggest potential underlying mechanisms and target genes regarding the immune system regulation in TNBC. Based on these insights, future research is warranted to develop targeted therapies, especially for immune-suppressed subtypes, aiming to improve clinical outcomes for patients with TNBC. Citation Format: Y. Cha, S. Bae, J. Kim, K. Kim, Y. Kook, A. Kim, S. Ahn, J. Jeon. Deciphering the tumor microenvironment related to immune regulation in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-29.