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PBMC single-cell transcriptome discriminates systemic immune changes associated with metastasis

ABSTRACT: Several single-cell studies have reported transcriptomic, genomic and epigenomic dysregulation in breast cancer tissue. However, the peripheral immune landscape of breast cancer patients remains poorly understood. We report the analysis of the single-cell transcriptomes of more than 110,000 peripheral blood mononuclear cells (PBMCs) of healthy and metastatic breast cancer patients. Integrated analysis revealed depleted memory B cells (BMEM) and T cell subpopulations, including transitional CD8 T, CD4 naïve, CD4 ribosome and MAIT cells in the circulating immune landscape of metastatic breast cancer patients. Nevertheless, metastatic breast cancer patients showed marked enrichment of pro-inflammatory NKG7 high monocytes, M1 macrophages, migratory myeloid, T memory stem cells (TSCM), CD4 T effector memory (TEM) and CD4 T central memory (TCM) cells. Further, interrogation of single-cell transcriptomes based on metastatic disease state, i.e. stable vs progressive, revealed distinct compositional and transcriptional changes in PBMCs correlated with the metastatic burden. The antigen inexperienced CD4 naïve T cells and cytotoxic MAIT cells are further depleted in the progressive metastatic stage. Surprisingly, the pro-inflammatory classical monocytes and CD4 T effector memory (TEM) cells are also depleted in the progressive metastatic state, indicating their potential role in stable metastatic disease. Lastly, the receptor-ligand relationships, such as cell-cell contact, ECM-receptor interactions, and cytokine transcription profiles, were tightly associated with metastatic burden. Collectively, our study provides unique molecular insight into the peripheral immune system operating in metastatic breast cancers and identified novel surrogate biomarkers of metastatic disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291055 | GEO | 2025/03/08

REPOSITORIES: GEO

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Project description:Persistence of memory CD4+ T cells in ECs was coupled with the inactivation of FOXO3a transcriptional activities, which we have previously identified as a critical regulator of TCM survival. Indeed, expression levels of transcriptional targets of FOXO3a, endowed with pro-apoptotic and anti-proliferative functions, were lower in TCM and TEM from ECs as compared to ST individuals. Silencing the transcriptionally active form of FOXO3a by siRNA rescued TCM and TEM of STs from Fas-mediated apoptosis. Moreover the expression of FOXO3a dominant negative form (FOXO3a Nt) rescued the long-term survival of TCM from STs as these cells persisted as long as those derived from ECs. Overall, these studies indicate that FOXO3a activation is an important mediator of the shortened survival and heighteined turnover of TCM and TEM in chronic HIV infection. Targeting this pathway may provide a strategy to preserve memory T cell numbers in HIV infection. Keywords: comparative gene profile, cell-type comparison Isolation of CD4+T cell sub-populations. Peripheral blood mononuclear cells (PBMCs) from healthy adult individuals were isolated by Ficoll-HyPaque (Pharmacia) density gradient. We first enriched for CD4+ T cells using negative immunomagnetic beads selection (Automacs, Myltenii), cells were then labeled with anti-CD4-APCcy7, anti-CD45RA-ECD, anti-CD27-FITC and anti-CCR7-PEcy7 and sorted into Naive cells described as CD4+, CD45RA+, CD27+ and CCR7+, Central Memory cells (TCM) described as CD4+, CD45RA-, CD27+ and CCR7+ cells and Effector Memory cells (TEM) described as CD4+, CD45RA-, CD27- and CCR7- cells. Sorting was performed using a BDAria (BD Pharmingen). Purity of the TCM and TEM sub-populations was ranging from 96 to 99%. All procedures were done at 4C to avoid any changes in cell phenotype or gene expression. Sample RNA was extracted using an RNA extraction kit (Quiagen), then amplified using the MessageAmp RNA kit (Ambion) as per the manufacturer’s instructions. The amplified RNA (aRNA) was then verified for quality and quantity using the Agilent Bioanalyser and measuring the OD. Universal human RNA (Stratagene) was also prepared in the same way. Sample probes were prepared by direct labelling with 3 µg of the aRNA Cy-5 (R values) fluorescent dye while the universal RNA probes were prepared by direct labelling of universal aRNA with Cy-3 (G values). All patient samples were hybridized against amplified universal RNA at 37 ºC for 18h on a custom human Immune array. Detailed information on the labeling and hybridization procedures can be obtained at the Microarray Centre web page (University Health Network).

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PBMC single-cell transcriptome discriminates systemic immune changes associated with metastasis

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