Resolving the immune landscape of human prostate at a single-cell level in health and cancer.
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ABSTRACT:
SUBMITTER: Tuong ZK
PROVIDER: S-EPMC8721283 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The prostate gland produces prostatic fluid, high in zinc and citrate and essential for the maintenance of spermatozoa. Prostate cancer is a common condition with limited treatment efficacy in castration-resistant metastatic disease, including with immune checkpoint inhibitors. We used single-cell RNA-sequencing to perform an unbiased assessment of the cellular landscape of human prostate and identified a previously unappreciated subset of tumour-enriched androgen receptor-negative luminal epithelial cells, with increased expression of cancer-associated genes. We also found a variety of innate and adaptive immune cells in normal prostate that were transcriptionally perturbed in prostate cancer. An exception was a unique, prostate-specific, zinc transporter-expressing macrophage population (MAC-MT), that contributed to tissue zinc accumulation in homeostasis, but showed enhanced inflammatory gene expression in tumours, including T cell-recruiting chemokines. Remarkably, enrichment of the MAC-MT signature in cancer biopsies was associated with improved disease-free survival, suggesting beneficial anti-tumour functions.
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Project description:Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4+ T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1β signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies.
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Project description:BackgroundDespite recent advances in cancer immunotherapy, the efficacy of these therapies for the treatment of human prostate cancer patients is low due to the complex immune evasion mechanisms (IEMs) of prostate cancer and the lack of predictive biomarkers for patient responses.MethodsTo understand the IEMs in prostate cancer and apply such understanding to the design of personalized immunotherapies, we analyzed the RNA-seq data for prostate adenocarcinoma from The Cancer Genome Atlas (TCGA) using a combination of biclustering, differential expression analysis, immune cell typing, and machine learning methods.ResultsThe integrative analysis identified eight clusters with different IEM combinations and predictive biomarkers for each immune evasion cluster. Prostate tumors employ different combinations of IEMs. The majority of prostate cancer patients were identified with immunological ignorance (89.8%), upregulated cytotoxic T lymphocyte-associated protein 4 (CTLA4) (58.8%), and upregulated decoy receptor 3 (DcR3) (51.6%). Among patients with immunologic ignorance, 41.4% displayed upregulated DcR3 expression, 43.26% had upregulated CTLA4, and 11.4% had a combination of all three mechanisms. Since upregulated programmed cell death 1 (PD-1) and/or CTLA4 often co-occur with other IEMs, these results provide a plausible explanation for the failure of immune checkpoint inhibitor monotherapy for prostate cancer.ConclusionThese findings indicate that human prostate cancer specimens are mostly immunologically cold tumors that do not respond well to mono-immunotherapy. With such identified biomarkers, more precise treatment strategies can be developed to improve therapeutic efficacy through a greater understanding of a patient's immune evasion mechanisms.
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Project description:COVID-19 is now causing a global pandemic, there is a demand to explain the different clinical patterns between children and adults. To clarify the organs/cell types vulnerable to COVID-19 infection and the potential age-depended expression patterns of five factors (ACE2, TMPRSS2, MTHFD1, CTSL, CTSB) associated with clinical symptoms. In this study, we analyzed expression levels of five COVID-19 host dependency factors in multiple adult and fetal human organs. The results allowed us to grade organs at risk and also pointed towards the target cell types in each organ mentioned above. Based on these results we constructed an organ- and cell type-specific vulnerability map of the expression levels of the five COVID-19 factors in the human body, providing insight into the mechanisms behind the symptoms, including the non-respiratory symptoms of COVID-19 infection and injury. Also, the different expression patterns of the COVID-19 factors well demonstrate an explanation that the different clinical patterns between adult and children/infants.
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Project description:BackgroundThis study was to explore the infiltration pattern of immune cells in the prostate cancer (PCa) microenvironment and evaluate the possibility of specific infiltrating immune cells as potential prognostic biomarkers in PCa.MethodsInfiltrating percentage of 22 immune cells were extracted from 27 normalized datasets by CIBERSORT algorithm. Samples with CIBERSORT p-value < 0.05 were subsequently merged and divided into normal or tumor groups. The differences of 22 immune cells between normal and tumor tissues were analyzed along with potential infiltrating correlations among 22 immune cells and Gleason grades. SNV data from TCGA was used to calculate the TMB score. A univariate and multivariate regression were used to evaluate the prognostic effects of immune cells in PCa.ResultsTen immune cells with significant differences were identified, including seven increased and three decreased infiltrating immune cells from 190 normal prostate tissues and 537 PCa tissues. Among them, the percentage of infiltration of resting NK cells increased the most, whereas the percentage of infiltration of resting mast cells decreased the most. In normal tissues, CD8+ T cells had the strongest infiltrating correlation with monocytes, while activated NK cells and naive B cells were the highest in PCa tissues. Moreover, the infiltration of five immune cells was significantly associated with TMB score and mutations of immune gene change the infiltration of immune cells. The Area Under Curve (AUC) of the multivariate regression model for the five- and 10-year survival prediction of PCa reached 0.796 and 0.862. The validation cohort proved that the model was reproducible.ConclusionsThis study demonstrated that different infiltrating immune cells in prostate cancer, especially higher infiltrating M1 macrophages and neutrophils in PCa tissue, are associated with patients' prognosis, suggesting that these two immune cells might be potential targets for PCa diagnosis and prognosis of treatment.
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Project description:BackgroundThe tumor-infiltrating immune cells are closely associated with the prognosis of gastric cancer (GC). This article is aimed at determining the composition change of immune cells and immune regulatory factors in GC and normal tissues, depicting their prognosis value in GC, and revealing the relationship between them and GC clinical parameters.MethodsWe used CIBERSORT to calculate the proportion of 22 immune cells in the GC or normal tissues; a t-test was applied to assess the expression difference of immune cells and immune regulatory factors in normal and GC tissues. The relationship of the immune cells, immune regulatory factors, and GC patients' clinical characteristics was assessed by univariate analysis.ResultsIn this study, we found that the proportion of macrophages increased, while plasma cells and monocytes decreased in GC tissues. In these immune fractions, Tregs and naïve B cells were found to be correlated with GC patients' prognosis. Interestingly, the expression of immune regulatory factors was ambiguous with their classical function in GC tissues. For example, TIM-3, FOXP3, and CMTM6 were overexpressed, while CD27 and PD-1 were underexpressed in GC tissues. We also found that IDO1, PD-1, TIGIT, and TIM-3 were highly expressed in high-grade GC tissues, the HERC2 expression level was related to patients' gender, and the TIGIT expression level was sensitive to targeted therapy. Furthermore, our results suggested that the infiltration of Tregs and naive B cells was strongly correlated with the T stage, radiation therapy, targeted molecular therapy, and the expression levels of TIM-3 and FOXP3 in GC.ConclusionThe expression pattern of tumor-infiltrating immune cells and immune regulatory factors was systematically depicted in the GC tumor microenvironment, indicating that individualized treatment based on the tumor-infiltrating immune cells and immune regulatory factors may be beneficial to GC patients.
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Project description:The tumor microenvironment is a complex ecosystem formed by distinct and interacting cell populations, and its composition is related to cancer prognosis and response to clinical treatment. In this study, we have taken the advantage of two single-cell RNA sequencing technologies (Smart-seq2 and DNBelab C4) to generate an atlas of 15,115 immune and nonimmune cells from primary tumors and hepatic metastases of 18 colorectal cancer (CRC) patients. We observed extensive changes in the proportions and functional states of T cells and B cells in tumor tissues, compared to those of paired non-tumor tissues. Importantly, we found that B cells from early CRC tumor were identified to be pre-B like expressing tumor suppressors, whereas B cells from advanced CRC tumors tended to be developed into plasma cells. We also identified the association of IgA+ IGLC2+ plasma cells with poor CRC prognosis, and demonstrated a significant interaction between B-cell and myeloid-cell signaling, and found CCL8+ cycling B cells/CCR5+ T-cell interactions as a potential antitumoral mechanism in advanced CRC tumors. Our results provide deeper insights into the immune infiltration within CRC, and a new perspective for the future research in immunotherapies for CRC.
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Project description:BackgroundImmune cells show distinct motion patterns that change upon inflammatory stimuli. Monocytes patrol the vasculature to screen for pathogens, thereby exerting an early task of innate immunity. Here, we aimed to non-invasively analyse single patrolling monocyte behaviour upon inflammatory stimuli.MethodsWe used time-lapse Magnetic Resonance Imaging (MRI) of the murine brain to dynamically track single patrolling monocytes within the circulation distant to the actual site of inflammation in different inflammatory conditions, ranging from a subcutaneous pellet model to severe peritonitis and bacteraemia.FindingsSingle patrolling immune cells with a velocity of <1 µm/s could be detected and followed dynamically using time-lapse MRI. We show, that due to local and systemic stimuli the slowly patrolling behaviour of monocytes is altered systemically and differs with type, duration and strength of the underlying stimulus.InterpretationUsing time-lapse MRI, it is now possible to investigate the behaviour of single circulating monocytes over the course of the systemic immune response. Monocyte patrolling behaviour is altered systemically even before the onset of clinical symptoms distant to and depending on the underlying inflammatory stimulus.FundingThis study was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - CRC 1009 - 194468054 to AZ, CF and - CRC 1450 - 431460824 to MM, SN, HB, AZ, CF, the Joachim Herz Foundation (Add-on Fellowship for Interdisciplinary Life Sciences to MM), the Interdisciplinary Centre for Clinical Research (IZKF, core unit PIX) and the Medical Faculty of the University of Muenster (MEDK fellowship to FF and IF).
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