CXCR2 Levels Correlate with Immune Infiltration and a Better Prognosis of Triple-Negative Breast Cancers.
Ontology highlight
ABSTRACT:
SUBMITTER: Boissiere-Michot F
PROVIDER: S-EPMC8151934 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Breast cancer represents the number one cause of cancer-associated mortality globally. The most aggressive molecular subtype is triple negative breast cancer (TNBC), of which limited therapeutic options are available. It is well known that breast cancer prognosis and tumor sensitivity toward immunotherapy are dictated by the tumor microenvironment. Breast cancer gene expression profiles were extracted from the METABRIC dataset and two TNBC clusters displaying unique immune features were identified. Activated immune cells formed a large proportion of cells in the high infiltration cluster, which correlated to a good prognosis. Differentially expressed genes (DEGs) extracted between two heterogeneous subtypes were used to further explore the underlying immune mechanism and to identify prognostic biomarkers. Functional enrichment analysis revealed that the DEGs were predominately related to some processes involved in activation and regulation of innate immune signaling. Using network analysis, we identified two modules in which genes were selected for further prognostic investigation. Validation by independent datasets revealed that CXCL9 and CXCL13 were good prognostic biomarkers for TNBC. We also performed comparisons between the above two genes and immune markers (CYT, APM, TILs, and TIS), as well as cell checkpoint marker expressions, and found a statistically significant correlation between them in both METABRIC and TCGA datasets. The potential of CXCL9 and CXCL13 to predict chemotherapy sensitivity was also evaluated. We found that the CXCL9 and CXCL13 were good predictors for chemotherapy and their expressions were higher in chemotherapy-responsive patients in contrast to those who were not responsive. In brief, immune infiltrate characterization on TNBC revealed heterogeneous subtypes with unique immune features allowed for the identification of informative and reliable characteristics representative of the local immune tumor microenvironment and were potential candidates to guide the management of TNBC patients.
| S-EPMC8017297 | biostudies-literature
Project description:ObjectiveTriple negative breast cancer (TNBC) is a kind of cancer that endangers the lives of women all over the world in the 21st century. Heat shock protein member 8 (HSPA8) is the chaperone gene of the heat shock protein family. It is involved in many cellular functions. For example, it promotes the circulation between ATP and ADP, participates in protein folding, and can change the vitality of the cell and inhibit its growth. However, the abnormal expression of HSPA8 gene in TNBC and its diagnostic and prognostic significance still need to be further studied.MethodsFirst, we used related databases (such as TCGA, GEO, GTEx, ONCOMINE, TIMER2.0, UALCAN, HPA, STRING, CCLE, and Kaplan-Meier plotter databases) to analyze the relationship between HSPA8 and TNBC by bioinformatics. Then, the analysis using only a small part of the experimental work is used to explain our findings. For example, HSPA8 protein expression was evaluated by immunohistochemical method in TNBC tissues. Western blotting experiments were carried out to verify the results. Then, the clinicopathological characteristics of patients with TNBC were analyzed by R software and Cox regression analysis. On the basis, a nomogram is constructed to estimate the 1-, 3-, and 5-year overall survival (OS). The prognostic nomogram performance was calibrated and evaluated by the calibration curve and receiver operating characteristic (ROC) curve.ResultsIn the study, we analyzed the three GEO databases (including GSE86945, GSE106977, and GSE102088) and found that HSPA8 is one of the central genes of TNBC. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) researches indicated that HSPA8 was mainly involved in partner-mediated autophagy, mRNA catabolism, neutrophil activation, immune response, protein targeting, RNA splicing, RNA catabolism, and other biological processes. Next, we used bioinformatics technology to find that the expression level of HSPA8 in breast cancer (BC) and TNBC samples was significantly higher than that in normal breast tissues, which was determined by analyzing hospital patient samples and related experiments. In addition, the expression level of HSPA8 in BC and TNBC samples was significantly correlated with clinical indexes such as TNM stage. The Cox analysis revealed that the expression of HSPA8 in TNBC had significant clinical prognostic value. The results of nomogram and ROC test show that HSPA8 has significant predictive ability in TNBC. The results of immune infiltration of HSPA8 through the TIMER2.0 database showed that there was a significant correlation between HSPA8 and immune cell subsets.ConclusionsOur results show that the expression of HSPA8 in TNBC has important clinical diagnostic significance and clarify the potential molecular mechanism that promotes the evolution of TNBC. The high expression of HSPA8 may be related with the poor clinical outcome of TNBC. This helps to provide us with a new direction of TNBC targeted therapy.
| S-EPMC9705114 | biostudies-literature
Project description:Proteasome dependency is a feature of many cancers that can be targeted by proteasome inhibitors. For some cancer types, notably breast cancer and triple-negative breast cancer (TNBC), high mRNA expression of a modified form of the proteasome, called the immunoproteasome (ImP), correlates with better outcomes and higher expression of one ImP subunit was associated with slower tumor growth in a small patient cohort. While these findings are in line with an anti-tumoral role of the ImP in breast cancer, studies investigating ImP expression at the protein level in large patient cohorts are lacking. Furthermore, while ImPs can be found in both immune and non-immune cells, the cellular source is often ignored in correlative studies. In order to determine the impact of ImP expression on breast cancer outcomes, we assessed the protein expression and cellular source of the ImP subunits PSMB8 and PSMB9 in a cohort of 2070 patients. Our data show a clear correlation between high ImP expression and better outcomes, most notably for TNBC patients and when tumor cells rather than stromal or immune cells express PSMB8 or PSMB9. Our results therefore suggest that ImP expression by tumor cells could be used as prognostic markers of TNBC outcomes.
| S-EPMC9902398 | biostudies-literature
Project description:BackgroundTriple-negative breast cancers (TNBCs) and basal-like breast cancers (BLBCs) are known as poor outcome subtypes with a lack of targeted therapy. Previous studies have shown conflicting results regarding the difference of prognostic significance between TNBCs and BLBCs. In this study, we aimed to characterize the prognostic features of TNBCs, in view of BLBCs and quintuple-negative breast cancers (QNBC/5NPs).MethodsUsing tissue microarray-based immunohistochemical analysis, we categorized 951 primary breast cancers into four or five subtypes according to the expression of ER, PR, HER2, and basal markers (CK5/6, EGFR).ResultsThe results of this study showed that both TNBCs and BLBCs were associated with high histological and/or nuclear grades. When the TNBCs are divided into two subtypes by the presence of basal markers, the clinicopathologic characteristics of TNBCs were mainly maintained in the BLBCs. The 5-subgrouping was the better prediction model for both disease free and overall survival in breast cancers than the 4-subgrouping. After multivariate analysis of TNBCs, the BLBCs did not have a worse prognosis than the QNBC/5NPs. Interestingly, the patients with BLBCs showed significant adjuvant chemotherapy benefit. In addition, QNBC/5NPs comprised about 6~8% of breast cancers in publicly available breast cancer datasetsConclusionThe QNBC/5NP subtype is a worse prognostic subgroup of TNBCs, especially in higher stage and this result may be related to adjuvant chemotherapy benefit of BLBCs, calling for caution in the identification of subgroups of patients for therapeutic classification.
| S-EPMC2957395 | biostudies-literature
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:Background and aimThe spatial distribution and interactions of cells in the tumor immune microenvironment (TIME) might be related to the different responses of triple-negative breast cancer (TNBC) to immunomodulators. The potential of multiplex IHC (m-IHC) in evaluating the TIME has been reported, but the efficacy is insufficient. We aimed to research whether m-IHC results could be used to reflect the TIME, and thus to predict prognosis and complement the TNBC subtyping system.MethodsThe clinical, imaging, and prognosis data for 86 TNBC patients were retrospectively reviewed. CD3, CD4, CD8, Foxp3, PD-L1, and Pan-CK markers were stained by m-IHC. Particular cell spatial distributions and interactions in the TIME were evaluated with the HALO multispectral analysis platform. Then, we calculated the prognostic value of components of the TIME and their correlations with TNBC transcriptomic subtypes and MRI radiomic features reflecting TNBC subtypes.ResultsThe components of the TIME score were established by m-IHC and demonstrated positive prognostic value for TNBC (p = 0.0047, 0.039, <0.0001 for DMFS, RFS, and OS). The score was calculated from several indicators, including Treg% in the tumor core (TC) or stromal area (SA), PD-L1+ cell% in the SA, CD3 + cell% in the TC, and PD-L1+ /CD8+ cells in the invasive margin and SA. According to the TNBC subtyping system, a few TIME indicators were significantly different in different subtypes and significantly correlated with MRI radiomic features reflecting TNBC subtypes.ConclusionWe demonstrated that the m-IHC-based quantitative score and indicators related to the spatial distribution and interactions of cells in the TIME can aid in the accurate diagnosis of TNBC in terms of prognosis and classification.
| S-EPMC10757132 | 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
Project description:MDM4 is one of the MDM protein family and is generally recognized as the key negative regulator of p53. As a cancer-promoting factor, it plays a non-negligible role in tumorigenesis and development. In this article, we analyzed the expression levels of MDM4 in pan-cancer through multiple databases. We also investigated the correlations between MDM4 expression and prognostic value, immune features, genetic mutation, and tumor-related pathways. We found that MDM4 overexpression is often accompanied by adverse clinical features, poor prognosis, oncogenic mutations, tumor-immune infiltration and aberrant activation of oncogenic signaling pathways. We also conducted transcriptomic sequencing to investigate the effect of MDM4 on transcript levels in colon cancer and performed qPCR to verify this. Finally, we carried out some in vitro experiments including colony formation assay, chemoresistance and senescence-associated β-galactosidase activity assay to study the anti-tumor treatment effect of small molecule MDM4 inhibitor, NSC146109. Our research confirmed that MDM4 is a prognostic biomarker and potential therapeutic target for a variety of malignancies.
| S-EPMC10821240 | biostudies-literature
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.
| S-EPMC5824276 | biostudies-literature
Project description:Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis. Sphingosine-1-phosphate (S1P), a potent sphingolipid metabolite, has been implicated in many processes that are important for breast cancer (BC). S1P signaling regulates tumorigenesis, and response to chemotherapy and immunotherapy by affecting the trafficking, differentiation or effector function of tumor-infiltrating immune cells (TIICs). Objective: In this study, using bioinformatics tools and publicly available databases, we have analyzed the prognostic value of S1P metabolizing genes and their correlation with TIICs in BC patients. Methods: The expression of S1P metabolizing genes and receptors was evaluated by the UALCAN cancer database. The correlation between mRNA expression of S1P metabolizing genes and receptors and survival outcome of breast cancer patients was analyzed by the Kaplan-Meier plotter database. The association between the gene expression and infiltration of immune cells in the tumors was analyzed by "Tumor-Infiltrating Immune Estimation Resource (TIMER). In silico protein expression analysis was done using the Human Protein Atlas" database. Results: TNBC patients with lower expression of S1P phosphatase 1 (SGPP1) or lipid phosphate phosphatase 3 (PLPP3) have much shorter relapse-free survival than the patients with a higher expression of these genes. SGPP1 and PLPP3 expression show a strong positive correlation with tumor-infiltrating dendritic cells (DCs), CD4+ and CD8+ T cells, neutrophils, and macrophages in the TNBC subtypes. In addition, S1P receptor 4 (S1PR4), an S1P receptor exhibit a strong positive correlation with DCs, CD4+ and CD8+ T cells and neutrophils in TNBC. We, therefore, conclude that low expression of SGPP1 and PLPP3 may hinder the recruitment of immune cells to the tumor environment, resulting in the blockage of cancer cell clearance and a subsequent poor prognosis.
| S-EPMC8255376 | biostudies-literature