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ObjectivesSkin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor.MethodsWe analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains.ResultsThe hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways.ConclusionsWe demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases.Trial registration number NCT01532869; Post-results.

Multiple studies have shown that cancer‐associated fibroblasts (CAFs) play an important role in tumour progression, including carcinogenesis, invasion, metastasis and the chemoresistance of cancer cells. Immune cells, including macrophages, natural killer cells, dendritic cells and T cells, play a dual role in the tumour microenvironment. Although increasing research has focused on studying interactions between distinct cells in the tumour microenvironment, the complex relationships between CAFs and immune cells remain unclear and need further study. Here, we summarize our current understanding of crosstalk between CAFs and immune cells, which may help clarify their diagnostic and therapeutic value in tumour progression.

Background Aging is the greatest risk factor for breast cancer, and although epithelial cells are the source of carcinomas, epithelial changes alone do not fully explain cancer susceptibility. Fibroblasts and macrophages are key stromal constituents around the cells of origin for cancer in breast tissue. With age, macrophages surrounding terminal ductal lobular units (TDLUs) become increasingly immunosuppressive. CD105 + fibroblasts intercalate within TDLUs, drive luminal differentiation, and give rise to immunosuppressive cancer-associated fibroblasts in other tissues. We propose that differences in fibroblasts are a crucial component of the stroma that shapes cancer susceptibility. Methods Primary peri-epithelial fibroblast cultures were established from prophylactic and reduction mammoplasties from 30 women ranging in age from 16 to 70 years and from  BRCA1 mutation carriers. Growth characteristics, transcriptional profiles, differentiation potential, and secreted proteins were profiled for fibroblast subtypes from diverse donors. Co-cultures with fibroblasts, macrophages, and T cells were used to ascertain the functional role played by CD105 + fibroblasts in immune cell modulation. Results We found that peri-epithelial CD105 + fibroblasts are enriched in older women as well as women who carry BRCA1 mutations. These CD105 + fibroblasts exhibit robust adipogenesis and secrete factors related to macrophage polarization. Macrophages cocultured with fibroblasts better maintain or enhance polarization states than media alone. CD105 + fibroblasts increased expression of immunosuppressive macrophage genes. CD105 + fibroblasts supported anti-inflammatory macrophage-mediated suppression of T cell proliferation, whereas CD105 − fibroblasts significantly reduced the suppressive effect of anti-inflammatory macrophages on T cell proliferation. Conclusions Establishment of a coculture system to dissect the molecular circuits between CD105 + fibroblasts and macrophages that drive immunosuppressive macrophage polarization has broad utility in understanding mammary gland development and events that precede cancer initiation. CD105 + fibroblasts and macrophages may coordinate to suppress immunosurveillance and increase breast cancer susceptibility.

The effects of stromal cell cultures isolated from breast cancer tissue on the differentiation and maturation of dendritic cells and proliferation of lymphocytes were studied in vitro . The derived cultures had the fibroblast-like morphology and carried mesenchymal markers CD73 and CD90 in the absence of epithelial (CD326, CD24) and macrophage (CD68) markers. The cells also expressed CD44, CD10, and CD29 and had low levels of HLA-ABC expression. Intracellular expression of fibroblast activation protein (FAP), tenascin C, and α-SMA indicated their activated state and stromal origin. Analysis of the functional properties of the cells revealed their ability to suppress differentiation of dendritic cells from monocytes, as well as the proliferation of T lymphocytes. However, they had no significant effect on DC maturation. The results demonstrate that fibroblasts in the tumor stroma of breast cancer may have a suppressive effect on important mechanisms of the adaptive immunity and can be involved in the process of tumor escape from the immunological control.

Pancreatic cancer (PC) is a highly aggressive pancreatic malignant tumor with poor prognosis due to its complex tumor microenvironment (TME) and metastatic potential. Fibroblasts play an important role in tumor progression and metastasis by remodeling the extracellular matrix (ECM) and influencing the immune response. This study explored migrasome-associated fibroblasts, especially TSPAN4 and ITGA5, as key regulators of pancreatic cancer metastasis, aiming to provide new ideas for therapeutic strategies targeting TME. We employed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to analyze pancreatic cancer tissues. Data from the GEO and TCGA databases were integrated and processed using batch correction techniques. Single-cell data were analyzed with Seurat and Monocle for dimensionality reduction and pseudotime trajectory analysis. Cell communication was assessed using CellCall and CellChat. Spatial transcriptomic analysis was conducted with RCTD and MISTy tools to investigate cell interactions within the TME. Additionally, gene enrichment, deconvolution, and prognostic analyses were performed, alongside experimental validation through siRNA transfection, qRT-PCR, and various functional assays to investigate the role of TSPAN4 in metastasis. Our results underscore the critical role of TSPAN4 fibroblasts in pancreatic cancer. These fibroblasts were predominantly located at the tumor periphery and exhibited elevated migrasome gene expression, which was associated with enhanced ECM remodeling and immune suppression. Intercellular communication analysis revealed that TSPAN4 fibroblasts engaged in extensive interactions with immune cells, such as macrophages and endothelial cells, facilitating metastasis and immune evasion. Moreover, the high expression of immune checkpoint markers indicated their involvement in modulating the immune response. TSPAN4 fibroblasts are key regulators of pancreatic cancer progression, contributing to metastasis, immune suppression, and ECM remodeling. Targeting these fibroblasts represents a promising therapeutic strategy to improve clinical outcomes and enhance the effectiveness of immunotherapies in pancreatic cancer.

FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

The skin serves as a physical barrier and an immunological interface that protects the body from the external environment 1 – 3 . Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body 4 – 6 . Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8 + T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8 + cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases. Single-cell analyses of skin samples from patients with vitiligo and functional genetic experiments in vitiligo mouse models show that distinct fibroblast subsets drive the organ level lesion patterns in this autoimmune disease.

The tumor microenvironment (TME) is a complex and ever-changing “rogue organ” composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens 1 . Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity 2 . However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence 3 – 5 . To advance our understanding of immunology outside the haematopoietic system, here we systematically investigate the regulation of immune genes in the three major types of structural cells: epithelium, endothelium and fibroblasts. We characterize these cell types across twelve organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin accessibility profiling and epigenome mapping. This comprehensive dataset revealed complex immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells. Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse. Structural cells implement a broad range of immune-regulatory functions beyond their roles as barriers and connective tissues, and they utilize an epigenetically encoded potential for immune gene activation in their rapid response to viral infection.

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 + T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing. Senescent cells increase with ageing and may cause inflammatory conditions, but how this accumulation is mediated is still unclear. Here the authors show that senescent cells express HLA-E to suppress NKG2A-mediated natural killer and CD8 T cell activation to avoid targeted elimination, while blocking NKG2A helps promote immunity against senescent cells.