Journal: Frontiers in Immunology

Article Title: Elevated Siglec-7 expression correlates with adverse clinicopathological, immunological, and therapeutic response signatures in breast cancer patients

doi: 10.3389/fimmu.2025.1573365

Figure Lengend Snippet: Elevated Siglec-7 transcript levels correlated with unfavorable clinicopathological outcomes in patients with invasive breast carcinoma, based on RNA-seq and microarray data from the TCGA (n = 1070) and METABRIC (n = 1980) cohorts. Log2 normalization was applied to the raw data counts from TCGA for visualization. (A, H) Siglec-7 mRNA relative expression is significantly increased in aggressive breast cancer PAM50 molecular profiles, notably TNBC within TCGA cohort and Claudin-low within METABRIC, compared to subtypes linked to favorable outcomes. (B, C, I, J) Siglec-7 gene shows a strong association with negative phenotypes of PR and ER biomarkers in both TCGA and METABRIC cohorts. (D, K) HER2 status showed no association with Siglec-7 transcripts in METABRIC dataset, but significant differences were observed in TCGA cohort (HER2+ vs. HER2-: p = 0.0119). (E, F) Breast tumors with advanced grade and higher stage exhibited a significant increase in Siglec-7 expression compared to those with less severe tumor profiles. (G) Aggressive ductal histological type exhibit markedly higher Siglec-7 transcript levels compared to lobular (p=0.0041). (L, M) Patients presenting poor prognostic index demonstrate significantly higher Siglec-7 expression compared to those with excellent (p = 0.0001), good (p < 0.0001), or moderate (p = 0.0298) scores. Kaplan–Meier analysis indicated that high Siglec-7 expression is linked to significantly diminished survival outcomes in breast cancer patients. *p < 0.01, **p < 0.01, ***p < 0.001, ****p < 0.0001, and ‘ns’ indicates no significance.

Article Snippet: In addition, for the TCGA clinicopathological assessment, PAM50 molecular subtyping and ER, PR, and HER2 status were sourced from The Cancer Immunome Atlas (TCIA) ( ) platform ( https://tcia.at/home ) and meticulously matched to patient IDs.

Techniques: RNA Sequencing, Microarray, Expressing

Journal: Frontiers in Immunology

Article Title: Elevated Siglec-7 expression correlates with adverse clinicopathological, immunological, and therapeutic response signatures in breast cancer patients

doi: 10.3389/fimmu.2025.1573365

Figure Lengend Snippet: Siglec-7 was linked to gene expression variations and was associated with signaling pathways and biological functions involved in breast cancer pathogenesis, as identified through differential gene and Gene Set Enrichment Analysis. (A) Volcano plot illustrating differentially expressed genes that are upregulated (green) or downregulated (red) in the Siglec-7 HIGH group across the TCGA and METABRIC datasets. The top 20 genes are labeled. (B) GSEA plots demonstrate statistically significant differences in predefined gene sets between Siglec-7 LOW and Siglec-7 HIGH groups. The plots identify pathways critical for breast cancer development, progression, and aggressiveness, with positive or negative enrichment observed in Siglec-7 HIGH TCGA patients. (C) Additional key biological processes associated with cancer proliferation, invasion, angiogenesis, and metastasis in TCGA Siglec-7 HIGH cluster are depicted in the bubble plot, utilizing molecular signatures from Hallmark, Ontology, and Curated databases. Terms with a nominal p-value < 0.05 and a false discovery rate (FDR) < 0.25 are considered statistically significant and represented. NES stands for Normalized Enrichment Score, and GO refers to Gene Ontology.

Article Snippet: In addition, for the TCGA clinicopathological assessment, PAM50 molecular subtyping and ER, PR, and HER2 status were sourced from The Cancer Immunome Atlas (TCIA) ( ) platform ( https://tcia.at/home ) and meticulously matched to patient IDs.

Techniques: Gene Expression, Protein-Protein interactions, Labeling

Journal: Frontiers in Immunology

Article Title: Elevated Siglec-7 expression correlates with adverse clinicopathological, immunological, and therapeutic response signatures in breast cancer patients

doi: 10.3389/fimmu.2025.1573365

Figure Lengend Snippet: Patients with elevated Siglec-7 expression exhibited a more immune-infiltrated tumor microenvironment and a positive enrichment of major immune function pathways. Estimate, TIDE, and GSEA analyses were used to assess the computed scores. (A, B) Siglec-7 expression correlates with a more complex breast tumor microenvironment, marked by increased cellular diversity with elevated immune and stromal scores, in addition to decreased T-cell exclusion in both TCGA and METABRIC patients. (C, D) GSEA and bar plots depicting significant positive enrichment of key immune biological processes in METABRIC Siglec-7 high patients. Statistical significance was determined at p < 0.05 and FDR < 0.25, with **** indicating p < 0.0001.

Article Snippet: In addition, for the TCGA clinicopathological assessment, PAM50 molecular subtyping and ER, PR, and HER2 status were sourced from The Cancer Immunome Atlas (TCIA) ( ) platform ( https://tcia.at/home ) and meticulously matched to patient IDs.

Techniques: Expressing

Journal: Frontiers in Immunology

Article Title: Elevated Siglec-7 expression correlates with adverse clinicopathological, immunological, and therapeutic response signatures in breast cancer patients

doi: 10.3389/fimmu.2025.1573365

Figure Lengend Snippet: Immune cell infiltration patterns in Siglec-7 high breast tumors reflected an immunosuppressive microenvironment. Immune cell fraction distributions were evaluated using the ImmunocellAI algorithm, with complementary analyses performed using Cibersort and Z-score signatures. (A) Immune cell distributions analyzed using ImmunocellAI in METABRIC and TCGA cohorts. (B) NK cell phenotype infiltration assessed with CIBERSORT in the TCGA dataset. (C) Profiles of immunosuppressive cells based on Z-score analysis. (D) Siglec-7 expression and its correlation with immune cell fractions in both METABRIC and TCGA cohorts. For statistical comparisons, Mann-Whitney U test was employed to determine significance between Siglec-7 low and high groups, while Spearman correlation coefficient was computed to evaluate associations. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, and ‘ns’ indicates no significant difference.

Article Snippet: In addition, for the TCGA clinicopathological assessment, PAM50 molecular subtyping and ER, PR, and HER2 status were sourced from The Cancer Immunome Atlas (TCIA) ( ) platform ( https://tcia.at/home ) and meticulously matched to patient IDs.

Techniques: Expressing, MANN-WHITNEY

Journal: Frontiers in Immunology

Article Title: Elevated Siglec-7 expression correlates with adverse clinicopathological, immunological, and therapeutic response signatures in breast cancer patients

doi: 10.3389/fimmu.2025.1573365

Figure Lengend Snippet: Siglec-7 overexpression correlated with the upregulation of a distinct inhibitory immune checkpoint profile across the tumor microenvironment and immune effector cells in breast cancer patients. (A) Siglec-7 expression demonstrates a significant positive correlation with the inhibitory immune checkpoint A2AR (r = 0.4293, p = 0.0036) in our in-house cohort, but not with VISTA (r = 0.09520, p = 0.9548), as assessed using RT-PCR. (B) Upregulation of inhibitory immune checkpoints and pro-tumoral molecules is associated with Siglec-7 high expression profile. In the heatmap, red indicates upregulation, while blue represents downregulation. (C) Patients with Siglec-7 HIGH breast tumors exhibited significant upregulation of several SIGLEC family members, with notable downregulation of SIGLEC4 (p < 0.0001, TCGA) and SIGLEC6 (p < 0.0001, METABRIC). (D) Siglec-7 expression is associated with an elevated gene expression profile of inhibitory checkpoints in NK cells, CD8+, and CD4+ T cells, revealing distinct immunoregulatory patterns in breast cancer patients. Intracellular gene expression levels were scaled using the antilog, where 1 denotes the lowest expression. Mann-Whitney U test was used to assess differences between Siglec-7 low and high groups, Spearman correlation coefficient to evaluate associations, and Welch’s t-test to compare mean gene expression profiles across groups, accounting for standard deviations and sample sizes. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, and ‘ns’ for no significant difference.

Article Snippet: In addition, for the TCGA clinicopathological assessment, PAM50 molecular subtyping and ER, PR, and HER2 status were sourced from The Cancer Immunome Atlas (TCIA) ( ) platform ( https://tcia.at/home ) and meticulously matched to patient IDs.

Techniques: Over Expression, Expressing, Reverse Transcription Polymerase Chain Reaction, Gene Expression, MANN-WHITNEY

Journal: Frontiers in Immunology

Article Title: Elevated Siglec-7 expression correlates with adverse clinicopathological, immunological, and therapeutic response signatures in breast cancer patients

doi: 10.3389/fimmu.2025.1573365

Figure Lengend Snippet: Patients exhibiting high Siglec-7 expression demonstrated resistance to conventional breast cancer therapies and limited response to immunotherapy. (A) Non-responders to chemotherapy (p = 0.0001, RFS) and endocrine therapy (p = 0.0066, pCR) show significantly elevated Siglec-7 expression compared to responders. (B) High Siglec-7 expression is significantly associated with a lower Immunophenoscore (IPS) and predicts a poorer response to conventional immunotherapy in TCGA patients. The immunophenogram illustrates the IPS parameters between Siglec-7 low and high expression groups. (C) Increased Siglec-7 levels are associated with reduced relative abundance of CE9 and CE10 in TCGA cohort, ecotypes linked to favorable trends in immunotherapy response. Red represents Siglec-7 HIGH group, while blue indicates Siglec-7 LOW . (D) High Siglec-7 expression in the TCGA cohort correlated with significant enrichment of pathways related to cancer therapy resistance. Significance was established using p < 0.05 and FDR < 0.25, with *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 and ‘ns’ for non-significant results.

Article Snippet: In addition, for the TCGA clinicopathological assessment, PAM50 molecular subtyping and ER, PR, and HER2 status were sourced from The Cancer Immunome Atlas (TCIA) ( ) platform ( https://tcia.at/home ) and meticulously matched to patient IDs.

Techniques: Expressing