Single-Cell RNA-Seq Reveals Immunosuppressive Effects of Triple-Negative Breast Cancer–Derived Exosomes on NK Cell Responses
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303346 | GEO | 2026/07/25
REPOSITORIES: GEO
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Project description:Triple-negative breast cancer (TNBC) is a highly aggressive and immunogenic subtype that lacks effective targeted therapies. Although tumor-derived exosomes are known to influence immune responses, their direct role in shaping human T cell plasticity and antigen specificity remains insufficiently characterized. In this study, we performed an integrative single-cell multiomic analysis of primary human T cells following exposure to exosomes isolated from 17 genomically distinct TNBC cell lines. By combining single-cell transcriptomics, T cell receptor (TCR) V(D)J sequencing, non-coding RNA profiling, and both bulk and single-cell cytokine analyses, we identified conserved and subtype-specific immunoregulatory programs elicited by TNBC-derived exosomes.
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Project description:Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer with limited targeted therapies. To model TNBC heterogeneity in an immunocompetent setting, we established syngeneic grafts derived from the TNBC MMTV-R26Met genetically engineered mouse model, which preserve both the molecular identity and immune landscape of primary tumors. These grafts recapitulate features of distinct TNBC subtypes, providing a physiologically relevant preclinical platform to investigate tumor–immune interactions and therapy response. Here, we performed single-cell RNA sequencing (scRNA-seq) on four syngeneic tumors (S34, S35, S37, and S39), generating transcriptomic profiles from 22,046 cells. Clustering identified cell populations spanning malignant epithelial, stromal, endothelial, and diverse immune subsets. Tumors displayed subtype-specific traits, including oxidative phosphorylation programs with N2-like neutrophils and epithelial–mesenchymal transition with M2-like macrophages. Despite overall low T cell infiltration, inhibitory receptors and myeloid checkpoint ligands were broadly expressed, highlighting strongly immunosuppressive microenvironments. These datasets provide a resource for dissecting TNBC subtype heterogeneity in an immunocompetent context and offer a preclinical framework to explore mechanisms of immune evasion and therapeutic response.
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Project description:Triple-negative breast cancer (TNBC) is the subtype of advanced breast cancer with the shortest survival time and the poorest prognosis, and treatment options are relatively limited. Exosomes, small extracellular vesicles enriched with bioactive molecules, are critical mediators of intercellular communication and have been implicated in cancer progression. The aim of this study was to investigate the molecular mechanism of exosomes promoting the proliferation and migration of TNBC.
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Project description:Background Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Methods A proteome profiler array was performed to identify secreted CXCL16 protein, the expression of which is regulated by ELK3 to control natural killer (NK) cell-mediated cytotoxicity. The correlation between ELK3 and CXCL16 was investigated by microarray and TCGA data analysis. NK cell cytotoxicity and migration assays were performed to examine the role of ELK3-CXCL16 in regulating the anticancer effect in TNBC. CXCL16-mediated NK cell recruitment and NK cell cytotoxicity were examined in an experimental metastasis mouse model and in an MDA-MB231 orthotopic mouse model. Results We show that targeting the ETS transcription factor ELK3 recruits immune cells including NK cells into tumors via the chemotactic activity of the chemokine. ELK3 depletion upregulated CXCL16 expression, thereby inducing NK cell recruitment to tumors and increasing NK cell cytotoxicity in TNBC . In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Conclusions The ELK3-CXCL16 axis regulates NK cell recruitment and increases NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.
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Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. The high malignancy of TNBC is contributed by its heterogeneity and enrichment of cancer stem cells. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Here, we identify TCOF1 as a novel super-enhancer-regulated gene that promotes TNBC growth and stemness. TCOF1, which plays a critical role in craniofacial development, is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. Whereas TCOF1 depletion has potent effects on the growth and stemness of basal-like TNBC, it has no effect on mesenchymal-like cells, highlighting the distinct molecular dependency in different subgroups of TNBC. Whole genome RNA sequencing uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that the upregulation of KIT by TCOF1 mediates TNBC stemness. These findings provide a rationale for developing therapeutics targeting TCOF1 in basal-like TNBC.
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Project description:Breast cancer is a major cause of cancer-associated mortality in females. Although therapeutic strategies targeting subtype-specific receptors have been developed for various breast cancer subtypes, effective targeted therapies for triple-negative breast cancer (TNBC) are lacking. Recently, the role of the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), in the progression and metastasis of breast cancer, especially TNBC, has attracted increasing attention. However, the role of exosomes secreted by CAFs in TNBC cell proliferation is poorly understood. Thus, in this study, we analyzed exosomes derived from both CAFs and MDA-MB-231 cells and identified exosomal miR-1290 as a key component. When delivered to TNBC cells (BT-549 and Hs578T), exosomal miR-1290 directly suppressed the expression of the putative tumor suppressor TBC1D4, which was accompanied by reduced TSC1 expression and activation of the mTOR pathway. The promotion of TNBC cell growth by miR-1290 through direct targeting of TBC1D4 was validated using 2D culture models, 3D spheroid models, and in vivo xenograft models. Furthermore, we demonstrated that treatment with the mTOR inhibitor rapamycin and the FDA-approved rapamycin analog everolimus effectively suppressed miR-1290-induced TNBC cell proliferation, suggesting a potential therapeutic strategy for TNBC. Moreover, in patient cohorts, elevated levels of circulating miR-1290 significantly distinguished patients with breast cancer from healthy individuals and correlated with poor survival outcomes. Therefore, miR-1290 and its direct target TBC1D4 have potential value in both targeted treatment and diagnosis of TNBC.
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Project description:Natural killer (NK) cells contribute to immunosurveillance and first-line defense in the control of tumor growth and metastasis diffusion. NKEVs are constitutively secreted, are biologically active, reflect the protein and genetic repertoire of their originating cells and exert anti-tumor activity in vitro and in vivo. NKEVs from tumor-conditioned NK cells interact with naïve NK cells promoting their cytotoxic activity. In cancer NK cells exhibit profound defects in degranulation ability, a status probably reflected by their NKEVs. Hence, NKEVs could contribute to improve cancer therapy by interacting with tumor and/or immune cells at the same time sensing the actual NK cell status in cancer patients. Here we investigated the role of NKEVs in stimulating the immune system and developed an immune enzymatic test (NKExoELISA) to sense the systemic NK cell status by measuring plasma NK-derived exosomes through combined capture of exosomes, expressing typical EV (tsg101) and NK cell (CD56) markers. We analyzed by LC-MS/MS the protein content from NKEVs evaluating proteins differentially expressed in exosomes (NKExo), vescicles (NKMV) and total cell extract (Tot extr) from parental NK cells. Proteomic data confirmed the presence of many EV markers and detected several proteins involved in immune response, cell adhesion and complement biological processes.
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