Dataset Information

3D Collagen Fiber Concentration Regulates Treg Cell Infiltration in Triple Negative Breast Cancer.

ABSTRACT:

Background

Triple negative breast cancer (TNBC) is characterized by poor prognosis and a lack of effective therapeutic agents owing to the absence of biomarkers. A high abundance of tumor-infiltrating regulatory T cells (Tregs) was associated with worse prognosis in malignant disease. Exploring the association between Treg cell infiltration and TNBC will provide new insights for understanding TNBC immunosuppression and may pave the way for developing novel immune-based treatments.

Materials and methods

Patients from TCGA were divided into Treg-high (Treg-H) and Treg-low (Treg-L) groups based on the abundance of Tregs according to CIBERSORT analysis. The association between expression level of Tregs and the clinical characteristics as well as prognosis of breast cancer were evaluated. Next, a Treg-related prognostic model was established after survival-dependent univariate Cox and LASSO regression analysis, companied with an external GEO cohort validation. Then, GO, KEGG and GSEA analyses were performed between the Treg-H and Treg-L groups. Masson and Sirius red/Fast Green staining were applied for ECM characterization. Accordingly, Jurkat T cells were encapsulated in 3D collagen to mimic the ECM microenvironment, and the expression levels of CD4, FOXP3 and CD25 were quantified according to immunofluorescence staining.

Results

The expression level of Tregs is significantly associated with the clinical characteristics of breast cancer patients, and a high level of Treg cell expression indicates a poor prognosis in TNBC. To further evaluate this, a Treg-related prognostic model was established that accurately predicted outcomes in both TCGA training and GEO validation cohorts of TNBC patients. Subsequently, ECM-associated signaling pathways were identified between the Treg-H and Treg-L groups, indicating the role of ECM in Treg infiltration. Since we found increasing collagen concentrations in TNBC patients with distant migration, we encapsulated Jurkat T cells within a 3D matrix with different collagen concentrations and observed that increasing collagen concentrations promoted the expression of Treg biomarkers, supporting the regulatory role of ECM in Treg infiltration.

Conclusion

Our results support the association between Treg expression and breast cancer progression as well as prognosis in the TNBC subtype. Moreover, increasing collagen density may promote Treg infiltration, and thus induce an immunosuppressed TME.

SUBMITTER: Gao H

PROVIDER: S-EPMC9237245 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceWhy some triple-negative breast cancers (TNBCs) have high and others have low immune cell infiltration is unknown. Understanding how immune surveillance shapes the cancer genome could help in the selection of patients and the development of more effective immunotherapy strategies.ObjectiveTo examine the association between genomic metrics and the extent of immune infiltration in TNBCs.Design, setting, and participantsThis study, performed from June 1, 2015, through January 31, 2017, used DNA and RNA sequencing data and messenger RNA expression results from The Cancer Genome Atlas (TCGA) breast cancer data set (n = 1215) to calculate previously described immune metagene expression values and histologic lymphocyte counts to quantify immune infiltration and assign prognostic categories to TNBCs. It used the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set as an independent validation cohort. The study compared clonal heterogeneity, somatic total mutational load, neoantigen load, and somatic copy number alteration levels between immune-rich TNBC cohorts with good prognosis and immune-poor TNBC cohorts with poor prognosis. The study also compared the distribution of mutations in 119 canonical cancer genes.Main outcomes and measuresCorrelation between immune prognostic category and genomic metrics of the cancer.ResultsThis study of 193 TNBC samples with patient survival information found an inverse association between clonal heterogeneity and immune metagene expression (ρ = −0.395, P = 2 × 10−8). The study also found an inverse association between immune metagene expression and somatic copy number alteration levels (ρ = −0.484, P = 2 × 10−10). Lymphocyte-rich TNBCs with good prognosis had significantly lower mutation and neoantigen counts than did lymphocyte-poor TNBCs with poor prognosis. The robustness of the study results was confirmed by using various immune metagenes in the same TCGA data set and in the independent METABRIC data set.Conclusions and relevanceThis study suggests that immune-rich TNBCs may be under an immune surveillance that continuously eliminates many immunogenic clones, resulting in lower clonal heterogeneity. These cancers may also represent the subset of TNBCs that could derive benefit from immune checkpoint inhibitor therapy to tilt the balance in favor of the immune system.