Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation.
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ABSTRACT:
SUBMITTER: Zheng H
PROVIDER: S-EPMC8269090 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, accounting for 10-20% of breast cancers with high intrinsic heterogeneity. Its unique immune microenvironment, including high expression of vascular endothelial growth factors, tumor infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a dual role in the occurrence, growth, and metastasis of TNBC. Understanding the TNBC microenvironment is of great significance for the prognosis and treatment of TNBC. In this article, we describe the composition and function of immune cells in the TNBC microenvironment and summarize the major cytokine growth factors and chemokines in the TNBC microenvironment. Finally, we discuss the progress of TNBC, cytokine-induced killer cell therapy, and immune checkpoint therapy.
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Project description:Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.
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Project description:We aimed to elucidate the landscape of tumor microenvironment (TME) in triple-negative breast cancer (TNBC). Cohorts from Gene Expression Omnibus database (N = 107) and METABRIC (N = 299) were used as the training set and validation set, respectively. TME was evaluated via single-sample gene set enrichment analysis, and unsupervised clustering was used for cluster identification. Consequently, TNBC was classified into two distinct TME clusters (Cluster 1 and Cluster 2) according to predefined immune-related terms. Cluster 1 was characterized by low immune infiltration with poor prognosis; whereas, Cluster 2 was characterized by high immune infiltration with better survival probability. Further, Cluster 1 had larger tumor volumes, while Cluster 2 had smaller tumor volumes. Finally, a TME signature for prognosis stratification in TNBC was developed and validated. In summary, we comprehensively evaluated the TME of TNBC and constructed a TME signature that correlated with prognosis. Our results provide new insights for the immunotherapy of TNBC.
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Project description:Acute-phase proteins (APPs) are associated with a variety of disorders such as infection, inflammatory diseases, and cancers. The signature profile of APPs in breast cancer (BC) is poorly understood. Here, we identified serum amyloid A (SAA) for proinflammatory predisposition in BC through the signature profiles of APPs, interleukin (IL) and tumor necrosis factor (TNF) superfamily using publicly available datasets of tumor samples and cell lines. Triple-negative breast cancer (TNBC) subtype highly expressed SAA1/2 compared to HER2, luminal A (LA) and luminal B (LB) subtypes. IL1A, IL1B, IL8/CXCL8, IL32 and IL27RA in IL superfamily and CD70, TNFSF9 and TNFRSF21 in TNF superfamily were highly expressed in TNBC compared to other subtypes. SAA is restrictedly regulated by nuclear factor (NF)-κB and IL-1β, an NF-κB activator highly expressed in TNBC, increased the promoter activity of SAA1 in human TNBC MDA-MB231 cells. Interestingly, two κB-sites contained in SAA1 promoter were involved, and the proximal region (-96/-87) was more critical than the distal site (-288/-279) in regulating IL-1β-induced SAA1. Among the SAA receptors, TLR1 and TLR2 were highly expressed in TNBC. Cu-CPT22, TLR1/2 antagonist, abrogated IL-1β-induced SAA1 promoter activity. In addition, SAA1 induced IL8/CXCL8 promoter activity, which was partially reduced by Cu-CPT22. Notably, SAA1/2, TLR2 and IL8/CXCL8 were associated with a poor overall survival in mesenchymal-like TNBC. Taken together, IL-1-induced SAA via NF-κB-mediated signaling could potentiate an inflammatory burden, leading to cancer progression and high mortality in TNBC patients.
| S-EPMC6355188 | biostudies-literature
Project description:BackgroundRecent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity.MethodsHere, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided.ResultsWe demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism.ConclusionsOur results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.
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Project description:Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.
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Project description:Liver kinase B1 (LKB1) is a potent tumor suppressor that regulates cellular energy balance and metabolism as an upstream kinase of the AMP-activated protein kinase (AMPK) pathway. LKB1 regulates cancer cell invasion and metastasis in multiple cancer types, including breast cancer. In this study, we evaluated LKB1’s role as a regulator of the tumor microenvironment (TME). This was achieved by seeding the MDA-MB-231-LKB1 overexpressing cell line onto adipose and tumor scaffolds, followed by the evaluation of tumor matrix-induced tumorigenesis and metastasis. Results demonstrated that the presence of tumor matrix enhanced tumorigenesis in both MDA-MB-231 and MDA-MB-231-LKB1 cell lines. Metastasis was increased in both MDA-MB-231 and -LKB1 cells seeded on the tumor scaffold. Endpoint analysis of tumor and adipose scaffolds revealed LKB1-mediated tumor microenvironment remodeling as evident through altered matrix protein production. The proteomic analysis determined that LKB1 overexpression preferentially decreased all major and minor fibril collagens (collagens I, III, V, and XI). In addition, proteins observed to be absent in tumor scaffolds in the LKB1 overexpressing cell line included those associated with the adipose matrix (COL6A2) and regulators of adipogenesis (IL17RB and IGFBP4), suggesting a role for LKB1 in tumor-mediated adipogenesis. Histological analysis of MDA-MB-231-LKB1-seeded tumors demonstrated decreased total fibril collagen and indicated decreased stromal cell presence. In accordance with this, in vitro condition medium studies demonstrated that the MDA-MB-231-LKB1 secretome inhibited adipogenesis of adipose-derived stem cells. Taken together, these data demonstrate a role for LKB1 in regulating the tumor microenvironment through fibril matrix remodeling and suppression of adipogenesis.
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