Deconvolution of regulatory T cell heterogeneity identifies cycling precursors as conductors of immune escape during breast carcinoma progression
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ABSTRACT:
ORGANISM(S): Rattus norvegicus Homo sapiens
PROVIDER: GSE253587 | GEO | 2026/02/26
REPOSITORIES: GEO
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Project description:Tumor-immune microenvironment is instrumental in shaping breast cancer tumor evolution. We previously identified an evolutionary bottleneck demarcating ductal carcinoma in situ (DCIS) from invasive ductal carcinoma (IDC). How the microenvironment evolves during such transition remains elusive. We dissected, in parallel, single-cell composition of DCIS and IDC patients and rat tumors that faithfully recapitulate human breast cancer. We discovered T cell diversity distinguishing DCIS and IDC and a novel cycling Treg state occupying the pseudotime bifurcation between DCIS and IDC, preceding more activated Treg subtypes. Multiscale analysis of patient cohorts as part of HTAN Consortium established that cycling Treg predicts recurrence in low-grade DCIS. We proved cycling Treg as Treg progenitors critical for immune escape and demonstrated that OX40 agonism restored immunotherapeutic sensitivity, where responders displayed increased inflammatory CAF subtype heterogeneity. Our study thus established cycling Treg’s importance in preserving immune escape and underscored its prognostic value to stratify future recurrence.
2026-02-26 | GSE312050 | GEO
Project description:Tumor-immune microenvironment is instrumental in shaping breast cancer tumor evolution. We previously identified an evolutionary bottleneck demarcating ductal carcinoma in situ (DCIS) from invasive ductal carcinoma (IDC). How the microenvironment evolves during such transition remains elusive. We dissected, in parallel, single-cell composition of DCIS and IDC patients and rat tumors that faithfully recapitulate human breast cancer. We discovered T cell diversity distinguishing DCIS and IDC and a novel cycling Treg state occupying the pseudotime bifurcation between DCIS and IDC, preceding more activated Treg subtypes. Multiscale analysis of patient cohorts as part of HTAN Consortium established that cycling Treg predicts recurrence in low-grade DCIS. We proved cycling Treg as Treg progenitors critical for immune escape and demonstrated that OX40 agonism restored immunotherapeutic sensitivity, where responders displayed increased inflammatory CAF subtype heterogeneity. Our study thus established cycling Treg’s importance in preserving immune escape and underscored its prognostic value to stratify future recurrence.
2026-02-26 | GSE253572 | GEO
Project description:Tumor-immune microenvironment is instrumental in shaping breast cancer tumor evolution. We previously identified an evolutionary bottleneck demarcating ductal carcinoma in situ (DCIS) from invasive ductal carcinoma (IDC). How the microenvironment evolves during such transition remains elusive. We dissected, in parallel, single-cell composition of DCIS and IDC patients and rat tumors that faithfully recapitulate human breast cancer. We discovered T cell diversity distinguishing DCIS and IDC and a novel cycling Treg state occupying the pseudotime bifurcation between DCIS and IDC, preceding more activated Treg subtypes. Multiscale analysis of patient cohorts as part of HTAN Consortium established that cycling Treg predicts recurrence in low-grade DCIS. We proved cycling Treg as Treg progenitors critical for immune escape and demonstrated that OX40 agonism restored immunotherapeutic sensitivity, where responders displayed increased inflammatory CAF subtype heterogeneity. Our study thus established cycling Treg’s importance in preserving immune escape and underscored its prognostic value to stratify future recurrence.
2026-02-26 | GSE253585 | GEO
Project description:Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generate the first single cell integrated map of chromatin accessibility and transcriptome in early embryos and demonstrate the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states. The ability to obtain these two layers of omics data will help provide more accurate definitions of "single cell state" and enable the deconvolution of regulatory heterogeneity from complex cell populations.
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Project description:Immunotherapy using checkpoint inhibitors is one of the most promising current cancer treatment strategies. However, in breast cancer, its success has been limited to a subset of patients with triple-negative disease, whose durability of observed responses remain unclear. The lack of detailed understanding of breast tumor immune evasion mechanisms and the treatment of patients with highly heterogeneous metastatic disease contribute to these disappointing results. Here we discuss the current knowledge about immune-related changes during breast tumor progression, with special emphasis on the in situ-to-invasive breast carcinoma transition that may represent a key step of immunoediting in breast cancer. Comprehensive characterization of early-stage disease and better understanding of immunologic drivers of disease progression will likely expand the tools available for immunotherapy and improve patient stratification.
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Project description:BackgroundIntratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance.MethodsHere, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy.ResultsAngiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts.ConclusionsThese results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment.Trial registrationThe study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.
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Project description:Studies have shown exosomal circRNAs can regulate the immune escape of tumors by carrying cancer-derived molecules. Regulatory T cells (Tregs) participate in the process of tumor immune escape. However, the mechanism by which exosomal circRNAs regulate Tregs to create a microenvironment for tumor immune escape is unclear. The effect of exosomes on the proliferation, migration, and invasion of tumor cells was evaluated by CCK-8, transwell, and wound-healing assays. The expression of circGSE1 was evaluated by real-time quantitative PCR, and the function of exosomal circGSE1 was explored by Western blot and RNA pull-down assays. In vivo animal metastasis models and bioluminescence imaging were used to verify the effect of exosomal circGSE1 on tumor progression. Collectively, we revealed that exosomal circGSE1 derived from hepatocellular carcinoma (HCC) cells promotes the progression of HCC by inducing Tregs expansion via regulating the miR-324-5p/TGFBR1/Smad3 axis. Therefore, in the future, exosomal circGSE1 can be used as a promising biomarker for immunotherapy of HCC.
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