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Stk11ec−/− mice develop a myeloid proliferative disorder with depressed DC differentiation a, b Flow cytometry analysis of spleen, lymph node (LN), and thymus cells isolated from WT or Stk11ec−/− mice and stained for CD11c, MHC II, and B220. Classical DCs (cDCs) were defined as CD11c⁺ MHC II⁺, plasmacytoid DCs (pDCs) were defined as CD11clow B220⁺. Bar graph summarizes cell number of cDC and pDC in spleen (n = 11–13 each group), LN (n = 11 each group), and thymus (n = 4–5 each group) (12-weeks-old, mixed-gender). †P = 0.006; *P < 0.001 versus WT by nonparametric Mann–Whitney U test (two-sided). c Flow cytometry analysis of spleen cells isolated from WT or Stk11ec−/− mice and stained for Lin (CD3, CD19, CD49b, Ly6G), B220, F4/80, and CD11b. Macrophages were defined as Lin⁻ B220⁻ F4/80⁺ CD11b⁺. Bar graph summarizes cell number of macrophage in spleen (n = 11–13 each group), LN (n = 4–5 each group), and thymus (n = 4–6 each group) (12-weeks-old, mixed-gender). †P = 0.003; *P < 0.001 versus WT by nonparametric Mann–Whitney U test (two-sided). d Flow cytometry analysis of bone marrow cells isolated from WT or Stk11ec−/− mice and stained for Lin (CD3, CD19, Ter119, NK1.1, B220), CD45, CD11c, MHC II, SIRP-α, and Flt3. Committed precursors of cDC (pre-cDC) were defined as Lin⁻ CD45⁺ CD11c⁺ MHC II⁻ SIRP-αint Flt3⁺. Bar graph summarizes cell number of pre-cDC in bone marrow (12-weeks-old, mixed-gender, n = 12–13 each group). *P < 0.001 versus WT by nonparametric Mann–Whitney U test (two-sided). e Flow cytometry analysis of bone marrow cells isolated from WT or Stk11ec−/− mice and stained for Lin, c-Kit, CD115, CX3CR1, and Flt3. Macrophages and DC precursors (MDPs) were defined as Lin⁻ c-Kithigh CD115⁺ CX3CR1⁺ Flt3⁺. Common DC precursors (CDPs) were defined as Lin⁻ c-Kitlow CD115⁺ Flt3⁺. Bar graph summarizes cell number of MDP/CDP in bone marrow (12-weeks-old, mixed-gender, n = 9–13 each group). †P = 0.002; *P < 0.001 versus WT by nonparametric Mann–Whitney U test (two-sided).
Source publication
In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of seri...
Citations
... Dendritic cells (DCs), distinguished leukocyte populations capable of initiating and regulating adaptive immune responses, are critical targets of cancer immunotherapy [144,145]. Deletion of serine/threonine kinase 11 (Stk11) in mouse ECs resulted in severe reductions of mature DC numbers and spontaneous tumor formation, indicating the crucial role of DCs in suppressing tumorigenesis [146]. Endothelial-like differentiation (ELD) of DCs represents a poorly studied mechanism contributing to tumor angiogenesis [147]. ...
The tumor microenvironment (TME) is a highly intricate milieu, comprising a multitude of components, including immune cells and stromal cells, that exert a profound influence on tumor initiation and progression. Within the TME, angiogenesis is predominantly orchestrated by endothelial cells (ECs), which foster the proliferation and metastasis of malignant cells. The interplay between tumor and immune cells with ECs is complex and can either bolster or hinder the immune system. Thus, a comprehensive understanding of the intricate crosstalk between ECs and immune cells is essential to advance the development of immunotherapeutic interventions. Despite recent progress, the underlying molecular mechanisms that govern the interplay between ECs and immune cells remain elusive. Nevertheless, the immunomodulatory function of ECs has emerged as a pivotal determinant of the immune response. In light of this, the study of the relationship between ECs and immune checkpoints has garnered considerable attention in the field of immunotherapy. By targeting specific molecular pathways and signaling molecules associated with ECs in the TME, novel immunotherapeutic strategies may be devised to enhance the efficacy of current treatments. In this vein, we sought to elucidate the relationship between ECs, immune cells, and immune checkpoints in the TME, with the ultimate goal of identifying novel therapeutic targets and charting new avenues for immunotherapy.
... LKB1 deficiency induces bone marrow failure and regulates hematopoietic stem cell survival [36]. Additionally, endothelial-cell-specific LKB1-deficient mice show tumor development, weight loss, and natural death [37]. Therefore, LKB1 may be involved in cell homeostasis and survival against oxidative stress and metabolic imbalance in RA. ...
Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients have increased reactive oxygen species (ROS) levels and an impaired redox balance compared with FLS from control patients. Liver kinase B1 (LKB1) plays a key role in ROS scavenging and cellular metabolism in various cancers. Here, we aimed to determine the specific mechanism of LKB1 in RA pathogenesis. FLS were obtained from RA patients (n = 10). siRNA-induced LKB1 deficiency in RA FLS increased ROS levels via NADPH oxidase 4 (NOX4) upregulation. RA FLS migration and expression of inflammatory factors, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF), were enhanced by LKB1 deficiency. LKB1-deficient RA FLS showed increased sensitivity to oxidative stress damage caused by hydrogen peroxidase exposure. siRNA-induced solute carrier family 7 member 11 (SLC7A11) deficiency in RA FLS enhanced NOX4 and ROS expression and increased cell migration. When LKB1-deficient RA FLS were stimulated with an AMP-activated protein kinase (AMPK) activator, the LKB1-inhibition-induced cell migration significantly decreased through the restoration of SLC7A11/NOX4 expression. LKB1 regulates the AMPK-mediated SLC7A11-NOX4-ROS pathway to control cell migration and inflammation. Our data indicate that LKB1 is a key regulator of redox homeostasis in RA FLS.
... Dynamic metabolic patterns are important characteristics of stem cells. [22][23][24][25] We found that most pathways of cluster 4 were related to the regulation of metabolism by KEGG analyses, suggesting the important characteristics of stem cells for cluster 4 ( Figure 3B). GO analyses also indicated that the DEGs of the identified RSC cluster 4 were related to visual system development processes ( Figure 3B). ...
Stem cell therapy is a promising strategy to rescue visual impairment caused by retinal degeneration. Previous studies have proposed controversial theories about whether in situ retinal stem cells (RSCs) are present in adult human eye tissue. Single‐cell RNA sequencing (scRNA‐seq) has emerged as one of the most powerful tools to reveal the heterogeneity of tissue cells. By using scRNA‐seq, we explored the cell heterogeneity of different subregions of adult human eyes, including pars plicata, pars plana, retinal pigment epithelium (RPE), iris, and neural retina (NR). We identified one subpopulation expressing SRY‐box transcription factor 2 (SOX2) as RSCs, which were present in the pars plicata of the adult human eye. Further analysis showed the identified subpopulation of RSCs expressed specific markers aquaporin 1 (AQP1) and tetraspanin 12 (TSPAN12). We, therefore, isolated this subpopulation using these two markers by flow sorting and found that the isolated RSCs could proliferate and differentiate into some retinal cell types, including photoreceptors, neurons, RPE cells, microglia, astrocytes, horizontal cells, bipolar cells, and ganglion cells; whereas, AQP1− TSPAN12− cells did not have this differentiation potential. In conclusion, our results showed that SOX2‐positive RSCs are present in the pars plicata and may be valuable for treating human retinal diseases due to their proliferation and differentiation potential. SOX2‐positive retinal stem cells (RSCs) are identified in adult human pars plicata. Using the specific surface markers aquaporin 1 and tetraspanin 12, the RSCs were isolated and proved to have proliferation and differentiation abilities.
... Numerous studies have shown that PTBP1, a protein coding gene, played essential roles in various cancers, including colorectal cancer, renal cell cancer, breast cancer, and glioma [26]. The PTBP1 performed functions through regulating of glycolysis, apoptosis, proliferation, tumorigenesis, invasion, and migration [27]. SLC39A proteins are ZIP metal ion transport proteins which mainly expressed on the plasma membrane in various tissues [28]. ...
Background:
mRNA became a promising therapeutic approach in many diseases. This study aimed to identify the tumor antigens specifically expressed in tumor cells for lower-grade glioma (LGG) and glioblastoma (GBM) patients.
Methods:
In this work, the mRNA microarray expression profile and clinical data were obtained from 301 samples in the Chinese Glioma Genome Atlas (CGGA) database, the mRNA sequencing data and clinical data of 701 samples were downloaded from The Cancer Genome Atlas (TCGA) database. Genetic alterations profiles were extracted from CGGA and cBioPortal datasets. R language and GraphPad Prism software were applied for the statistical analysis and graph work.
Results:
PTBP1 and SLC39A1, which were overexpressed and indicated poor prognosis in LGG patients, were selected as tumor-specific antigens for LGG patients. Meanwhile, MMP9 and SLC16A3, the negative prognostic factors overexpressed in GBM, were identified as tumor-specific antigens for GBM patients. Besides, three immune subtypes (LGG1-LGG3) and eight WGCNA modules were identified in LGG patients. Meanwhile, two immune subtypes (GBM1-GBM2) and 10 WGCNA modules were selected in GBM. The immune characteristics and potential functions between different subtypes were diversity. LGG2 and GBM1 immune subtype were associated with longer overall survival than other subtypes.
Conclusion:
In this study, PTBP1 and SLC39A1 are promising antigens for mRNA vaccines development in LGG, and MMP9 and SLC16A3 were potential antigens in GBM. Our analyses indicated that mRNA vaccine immunotherapy was more suitable for LGG2 and GBM1 subtypes. This study was helpful for the development of glioma immunotherapies.
... EC cytokine production may not only affect IC extravasation but also IC functional properties. Glioblastoma EC produce large amounts of IL-6 that influence the properties of perivascular macrophages, creating a more pro-tumoral microenvironment [65] and dendritic cell maturation requires EC stem cell factor production [66]. ...
The vasculature plays a major role in regulating the tumor immune cell response although the underlying mechanisms explaining such effects remain poorly understood. This review discusses current knowledge on known vascular functions with a viewpoint on how they may yield distinct immune responses. The vasculature might directly influence selective immune cell infiltration into tumors by its cell surface expression of cell adhesion molecules, expression of cytokines, cell junction properties, focal adhesions, cytoskeleton and functional capacity. This will alter the tumor microenvironment and unleash a plethora of responses that will influence the tumor’s immune status. Despite our current knowledge of numerous mechanisms operating, the field is underexplored in that few functions providing a high degree of specificity have yet been provided in relation to the enormous divergence of responses apparent in human cancers. Further exploration of this field is much warranted.
The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.
Liver kinase B1 (Lkb1), encoded by serine/threonine kinase ( Stk11 ), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz–Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal‐specific Lkb1 is sufficient for the development of PJS‐like polyps in mice. However, the cellular origin and components of these Lkb1‐associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen‐inducible Lkb1 flox/flox ; Myh11‐Cre/ERT2 and Lkb1 flox/flox ; PDGFRα‐Cre/ERT2 mice, performed single‐cell RNA sequencing (scRNA‐seq) and imaging‐based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1 flox/+ ; Myh11‐Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA‐seq revealed aberrant stem cell‐like characteristics of epithelial cells from polyp tissues of Lkb1 flox/+ ; Myh11‐Cre/ERT2 mice. The Lkb1‐associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1–Cd44 or Spp1–Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1‐associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen‐inducible Lkb1 flox/flox ; PDGFRα‐Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2–3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1‐associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.
