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Project description:Background-Triple-negative breast cancer is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors contribute to its treatment response, but the inherent molecular and cellular tumor heterogeneity are increasingly acknowledged as crucial determinants.Methods-Spatial transcriptomic profiling was performed on FFPE tissues from a retrospective, treatment-naive group of women with differential prognoses (17 with >15 years survival- good prognosis (GPx) and 15 with <3 years survival-poor prognosis (PPx)) using GeoMX® Digital Spatial Profiler. Regions of interest were segmented on pan-cytokeratin and analyzed for tumor and stromal components, probed using GeoMx human whole transcriptome atlas (WTA) panel. Data quality control, normalization, and differential analysis was performed in R using GeomxTools and linear mixed models. Additional analyses including cell-type deconvolution, spatial entropy, functional enrichment, TF-target / ligand-receptor analysis and convolution neural networks were employed to identify significant gene signatures contributing to differential prognosis.Results-Here we report on the spatial and molecular heterogeneity underlying differential prognosis. We observe that the state of the epithelia and its microenvironment (TME) are transcriptionally distinct between the two groups. Invasive epithelia in GPx show a significant increase in immune transcripts with the TME exhibiting increased immune cell presence (via IF), while in PPx they are more metabolically and translationally active, with the TME being more mesenchymal/fibrotic. Specifically, pre-cancerous epithelia in PPx display a prescience of aggressiveness as evidenced by increased EMT-signaling. We identify distinct epithelial gene signatures for PPx and GPx, that can, with high accuracy, classify samples at the time of diagnosis and likely inform therapy.Conclusions-To the best of our knowledge, this is the first study to leverage spatial transcriptomics for an in-depth delineation of the cellular and molecular underpinnings of differential prognosis in TNBC. Our study highlights the potential of spatial transcriptomics to not only uncover the molecular drivers of differential prognosis in TNBC but also to pave the way for precision diagnostics and tailored therapeutic strategies, transforming the clinical landscape for this aggressive breast cancer subtype.
| S-EPMC11844391 | biostudies-literature
Project description:Triple-negative breast cancer is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors contribute to its treatment response, but the inherent molecular and cellular tumor heterogeneity are increasingly acknowledged as crucial determinants. Here we report on the spatial and molecular heterogeneity underlying a retrospective, treatment-naïve group of women with differential prognoses (17 with >15 years survival- good prognosis (GPx) and 15 with <3 years survival-poor prognosis (PPx)) profiled using GeoMX® DSP. Analyses revealed that the state of epithelia and its microenvironment (TME) are transcriptionally distinct between the two groups. Invasive epithelia in GPx shows a significant increase in immune transcripts, with the TME exhibiting increased immune cell presence (via IF). PPx epithelia, in contrast, are more metabolically and translationally active, with the TME being more mesenchymal/fibrotic. Notably, pre-cancerous epithelia in PPx display a prescience of aggressiveness, as evidenced by increased EMT-signaling. We identify distinct epithelial gene signatures for PPx and GPx, that can, with high accuracy, classify samples at the time of diagnosis and are likely to inform therapy.
2025-12-19 | GSE295858 | GEO
Project description:Triple-negative breast cancer is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors contribute to its treatment response, but the inherent molecular and cellular tumor heterogeneity are increasingly acknowledged as crucial determinants. Here we report on the spatial and molecular heterogeneity underlying a retrospective, treatment-naïve group of women with differential prognoses (17 with >15 years survival- good prognosis (GPx) and 15 with <3 years survival-poor prognosis (PPx)) profiled using GeoMX® DSP. Analyses revealed that the state of epithelia and its microenvironment (TME) are transcriptionally distinct between the two groups. Invasive epithelia in GPx shows a significant increase in immune transcripts, with the TME exhibiting increased immune cell presence (via IF). PPx epithelia, in contrast, are more metabolically and translationally active, with the TME being more mesenchymal/fibrotic. Notably, pre-cancerous epithelia in PPx display a prescience of aggressiveness, as evidenced by increased EMT-signaling. We identify distinct epithelial gene signatures for PPx and GPx, that can, with high accuracy, classify samples at the time of diagnosis and are likely to inform therapy.
2025-12-19 | GSE295927 | GEO
Project description:Spatially distinct cellular and molecular landscapes define prognosis in triple negative breast cancer
| PRJNA1256808 | ENA
Project description:Spatially distinct cellular and molecular landscapes define prognosis in triple negative breast cancer [2]
| PRJNA1256802 | ENA
Project description:Spatially distinct cellular and molecular landscapes define prognosis in triple negative breast cancer [1]
| PRJNA1256504 | ENA
Project description:Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+CD8+ T cells (GzmB+CD8+ T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An "immune-cold" microenvironment with an absence of tumoral CD8+ T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8+ T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC.
| S-EPMC6436884 | biostudies-literature
Project description:PurposeProgrammed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor-immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1- TNBC.Experimental designFrom a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1- TNBC, as defined by FDA-approved PD-L1 companion assays.Results228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation-related proteins correlated most strongly with PD-L1 protein.ConclusionsIn this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC.See related commentary by Symmans, p. 5446.
| S-EPMC8808363 | biostudies-literature
Project description:Triple negative breast cancers (TNBCs) are characterized by worse prognosis, higher propensity to earlier metastases, and shorter survival after recurrence compared with other breast cancer subtypes. Anthracycline- and taxane-based chemotherapy is still the mainstay of treatment in early stages, although several escalation approaches have been evaluated to improve survival outcomes. The addition of platinum salts to standard neoadjuvant chemotherapy (NACT) remains controversial due to the lack of clear survival advantage, and the use of adjuvant capecitabine represents a valid treatment option in TNBC patients with residual disease after NACT. Recently, several clinical trials showed promising results through the use of poly ADP-ribose polymerase (PARP) inhibitors and by incorporating immunotherapy with chemotherapy, enriching treatment options beyond conventional cytotoxic agents. In this review, we provided an overview on the current standard of care and a comprehensive update of the recent advances in the management of early stage TNBC and focused on the latest emerging biomarkers and their clinical application to select the best therapeutic strategy in this hard-to-treat population.
| S-EPMC7225917 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Recent studies have shown that MHC class II (MHCII) expression and tumor infiltrating lymphocytes are important prognostic factors in patients with TNBC, although the relative importance of lymphocyte subsets and associated protein expression is incompletely understood. NanoString Digital Spatial Profiling (DSP) allows for spatially resolved, highly multiplexed quantification of proteins in clinical samples. In this study, we sought to determine if DSP could be used to characterize expression of MHCII and other immune related proteins in tumor epithelial versus stromal compartments of patient-derived TNBCs (N = 10) using a panel of 39 markers. We confirmed that a subset of TNBCs have elevated expression of HLA-DR in tumor epithelial cells; HLA-DR expression was also significantly higher in the tumors of patients with long-term disease-free survival when compared to patients that relapsed. HLA-DR expression in the epithelial compartment was correlated with high expression of CD4 and ICOS in the stromal compartment of the same tumors. We also identified candidate protein biomarkers with significant differential expression between patients that relapsed versus those that did not. In conclusion, DSP is a powerful method that allows for quantification of proteins in the immune microenvironment of TNBCs.
| S-EPMC7170957 | biostudies-literature