Systemic chemotherapy in metastatic TNBC polarizes effector T cell differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE291111 | GEO | 2025/11/21
REPOSITORIES: GEO
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Project description:Systemic chemotherapy in metastatic TNBC polarizes effector T cell differentiation
| PRJNA1231596 | ENA
Project description:Due to scarcity of effective therapeutic targets, metastatic TNBC (mTNBC) has shorter survival times compared to other advanced breast cancer subtypes. Although chemo-immunotherapy with immune checkpoint inhibitors (ICIs) in PD-L1+ mTNBC has shown promise, survival benefit remains modest. Therefore, it is crucial to gain improved insight into the mechanisms underlying response and resistance to checkpoint inhibition in mTNBC. We employed single cell-RNA-sequencing, single cell secretomics, and flow cytometry to identify transcriptomic and proteomic peripheral immune cell signatures associated with response and non-response to anti-PD-1/PD-L1 therapy and chemotherapy in mTNBC. Transcriptomic analysis revealed divergent transcriptional programming of CD33+ myeloid cells between responders and non-responders, even in pretreatment PBMC samples. This divergence, in responders, was characterized by an immune-promoting CD33+ cell phenotype involving IL-1b signaling versus, in non-responders, an immunosuppressive phenotype marked by IL-1b inhibition. These baseline differences expanded during the course of treatment. Differences in CD33+ cell phenotype resulted in functional differences in lymphocyte activities between responders and non-responders. To confirm this causal role of myeloid cells, we depleted CD33+ cells in pre-treatment samples from non-responders, which led to a rescue of T cell effector function. Our findings highlight CD33+ cell phenotype as a key determinant of response to chemo-immunotherapy, which can be assessed from peripheral blood. This offers a valuable tool in the context of metastatic TNBC, in which tissue sampling is often challenging.
2024-10-31 | GSE270235 | GEO
Project description:Single-cell RNA-seq (scRNA-seq) of pancreatic islets have reported on α- and β-cell gene expression in mice and subjects of predominantly European ancestry. We aimed to assess these findings in East-Asian islet-cells. 448 islet-cells were captured from three East-Asian non-diabetic subjects for scRNA-seq. Hierarchical clustering using pancreatic cell lineage genes was used to assign cells into cell-types. Differentially expressed transcripts between α- and β-cells were detected using ANOVA and in silico replications of mouse and human islet cell genes were performed. We identified 118 α, 105 β, 6 δ endocrine cells and 47 exocrine cells. Besides INS and GCG, 26 genes showed differential expression between α- and β-cells. 10 genes showed concordant expression as reported in rodents, while FAM46A was significantly discordant. Comparing our East-Asian data with data from primarily European subjects, we replicated several genes implicated in nuclear receptor activations, acute phase response pathway, glutaryl-CoA/tryptophan degradations and EIF2/AMPK/mTOR signaling. Additionally, we identified protein ubiquitination to be associated among East-Asian β-cells. We report on East-Asian α- and β-cell gene signatures and substantiate several genes/pathways. We identify expression signatures in East-Asian β-cells that perhaps reflects increased susceptibility to cell-death and warrants future validations to fully appreciate their role in East-Asian diabetes pathogenesis.
2017-08-11 | GSE97655 | GEO
Project description:Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.
| S-EPMC8583122 | biostudies-literature
Project description:Cancer dysregulates intratumoral innate-adaptive immune cell crosstalk, but it remains largely unknown how the systemic immune landscape is modified during breast cancer progression. Here, we comprehensively profiled the circulating immune profile of patients with stage I-III or stage IV triple-negative breast cancer (TNBC) and healthy donors (HDs). We showed that patients with metastatic TNBC (mTNBC) exhibited decreased numbers of circulating T cells, dendritic cell subsets and differentiated B cells compared to patients with stage I-III TNBC and HDs, which was partially associated with prior chemotherapy. Moreover, increased IL17 production by vδ1 γδ T cells was observed in patients with mTNBC compared to HDs. Classical monocytes and neutrophils were increased in patients with mTNBC compared to HDs, irrespective of prior chemotherapy. Transcriptional and proteomic analysis, alongside ex vivo functionality assays, revealed increased migratory capacity, increased abundance of granule proteins, and elevated ROS production in circulating neutrophils from mTNBC patients. Some of these systemic immune alterations, including decreased levels of non-switched B cells and increased migratory capacity of neutrophils, were already evident in patients with stage I-III TNBC. Our data underscore the significant impact of TNBC disease stage on the systemic immune composition and function.
2025-01-25 | GSE264108 | GEO
Project description:East-Asian (EA) patients with Non Small Cell Lung Cancer (NSCLC) are associated with a high proportion of non-smoking women, EGFR activating somatic mutations, and clinical responses to tyrosine kinase inhibitors. We identify copy number alterations specific to EA and Western European (WE) NSCLCs and conducted an integrative analysis using transcritomic data for identifying copy-number-driven candidate genes. Samples were hybridized to Affymetrix Genome-Wide Human SNP 6.0 arrays according to the manufacturer’s specifications in the same center. 226 lung adenocarcinomas (90 East-Asian and 136 Western-European) were analyzed for copy-number aberrations (CNAs) using a common high resolution SNP microarray platform.
2011-11-22 | E-GEOD-33848 | biostudies-arrayexpress
Project description:Patients diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunostimulatory metronomic Cytoxan (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic syngeneic Trp53 null TNBC genetically engineered mouse models (GEMMs) that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-15 and type II interferon and elevated B- and T cells. Addition of an anti-PD-1 maintenance dose was necessary to overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.
2025-12-05 | GSE292908 | GEO
Project description:There exists a common deletion polymorphism on the genetic loci of APOBEC3B and this polymorphism exist in ~37% of East Asians and ~7% of Europeans. Germline APOBEC3B deletion has bee27233495n shown to confer modest risk to breast cancer in both East Asian women and women of European descent We performed expression profiling by array to investigate the significantly differentially expressed genes and enriched gene sets in APOBEC3B-null vs. APOBEC3B breast cancers
2016-09-18 | GSE73540 | GEO
Project description:Cancer dysregulates intratumoral adaptive-innate immune cell crosstalk, however, it remains largely unknown how the systemic immune landscape is modified during breast cancer progression and whether prior chemotherapy treatment exerts persistent changes on circulating immune cells. Here, we comprehensively profiled the systemic immune landscape in patients with triple negative breast cancer (TNBC) at distinct disease stages, to understand how cancer progression and treatment history shape the systemic immune landscape. We performed multi-parameter flow cytometry analysis to assess the global systemic immune landscape, including often overlooked granulocytes. We showed that patients with metastatic TNBC (mTNBC) exhibited increased classical monocytes and neutrophils compared to healthy donors (HDs) irrespective of prior therapy. Conversely, circulating T cells, dendritic cell subsets and differentiated B cells were reduced in patients with mTNBC compared to HDs, which could partially be attributed to prior chemotherapy treatment. Phenotypic and functional characterization of the T cell compartment revealed increased IL17 production by vδ1 γδ T cells, were increased. Transcriptional and proteomic analysis, alongside ex vivo functionality assays, revealed increased migratory capacity, increased granule proteins, and elevated ROS production in circulating neutrophils of mTNBC patients. Our data demonstrate that patient neutrophils are not only more abundant, but also display an altered functionality, underscoring the significant impact of TNBC disease stage and treatment history on the systemic immune composition and function.
2025-04-09 | PXD051334 | Pride
Project description:Spotted hyena (Crocuta crocuta) is the only extant species of the genus Crocuta, which once occupied a much wider range during the Pliocene and Pleistocene. However, its origin and evolutionary history is somewhat contentious due to discordances being found between morphological, nuclear, and mitochondrial data. Due to the limited molecular data from east Asian Crocuta, and the difficulty of extracting ancient DNA from this area, here we present proteomic analysis of cave hyenas from three locations in northern China. This marks the first proteomic data generated from cave hyenas, adding new molecular data to the east Asian populations. Phylogenetic analysis based on these protein sequences reveals two different groups of cave hyenas in east Asia, one of which could not be distinguished from modern spotted hyenas from northern Africa, tentatively the result of previously suggested gene flow between these lineages. With developments of instrumentation and analytical methods, proteomics holds promising potential for the phylogenetic reconstruction of ancient fauna previously thought to be unreachable using ancient DNA.
2020-10-19 | PXD020530 | Pride