scholarly journals Mapping the immune microenvironment for mandibular alveolar bone homeostasis at single-cell resolution

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Weimin Lin ◽  
Qiwen Li ◽  
Danting Zhang ◽  
Xiaohan Zhang ◽  
Xingying Qi ◽  
...  
Keyword(s):  
Single Cell ◽  
Alveolar Bone ◽  
Immune Cell ◽  
Adipogenic Differentiation ◽  
Oncostatin M ◽  
Long Bone ◽  
Bone Homeostasis ◽  
Oral Diseases ◽  
Immune Microenvironment ◽  
Occlusal Force

AbstractAlveolar bone is the thickened ridge of jaw bone that supports teeth. It is subject to constant occlusal force and pathogens invasion, and is therefore under active bone remodeling and immunomodulation. Alveolar bone holds a distinct niche from long bone considering their different developmental origin and postnatal remodeling pattern. However, a systematic explanation of alveolar bone at single-cell level is still lacking. Here, we construct a single-cell atlas of mouse mandibular alveolar bone through single-cell RNA sequencing (scRNA-seq). A more active immune microenvironment is identified in alveolar bone, with a higher proportion of mature immune cells than in long bone. Among all immune cell populations, the monocyte/macrophage subpopulation most actively interacts with mesenchymal stem cells (MSCs) subpopulation. Alveolar bone monocytes/macrophages express a higher level of Oncostatin M (Osm) compared to long bone, which promotes osteogenic differentiation and inhibits adipogenic differentiation of MSCs. In summary, our study reveals a unique immune microenvironment of alveolar bone, which may provide a more precise immune-modulatory target for therapeutic treatment of oral diseases.

scholarly journals Single Cell Atlas of Human Dura Reveals Cellular Meningeal Landscape and Insights into Meningioma Immune Response

2021 ◽  
Author(s):  
Anthony Z Wang ◽  
Jay Bowman-Kirigin ◽  
Rupen Desai ◽  
Pujan Patel ◽  
Bhuvic Patel ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Copy Number Variant ◽  
Cell Types ◽  
Cell Receptor ◽  
Immune Microenvironment ◽  
Clinical Models ◽  
Insight Into

Recent investigation of the meninges, specifically the dura layer, has highlighted its importance in CNS immune surveillance beyond a purely structural role. However, most of our understanding of the meninges stems from the use of pre-clinical models rather than human samples. In this study, we use single cell RNA-sequencing to perform the first characterization of both non-tumor-associated human dura and meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, through T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. We also identify a functionally heterogeneous population of non-immune cell types and report copy-number variant heterogeneity within our meningioma samples. Our comprehensive investigation of both the immune and non-immune cell landscapes of human dura and meningioma at a single cell resolution provide new insight into previously uncharacterized roles of human dura.

IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi92
Author(s):  
Mirco Friedrich ◽  
Lukas Bunse ◽  
Roman Sankowski ◽  
Wolfgang Wick ◽  
Marco Prinz ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Tumor Evolution ◽  
Large Neutral Amino Acid ◽  
Immune Microenvironment ◽  
Idh Mutations

Abstract The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.

39 Spatial single-cell quantitative analyses of human head and neck squamous cell carcinomas

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A40-A40
Author(s):  
Katie Blise ◽  
Shamilene Sivagnanam ◽  
Lisa Coussens ◽  
Jeremy Goecks
Keyword(s):  
Head And Neck ◽  
Single Cell ◽  
Tumor Cells ◽  
Spatial Organization ◽  
Immune Cell ◽  
Human Head ◽  
Squamous Cell Carcinomas ◽  
Cellular Composition ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

BackgroundWhile the quantities and types of immune, tumor, and structure-related cells present in the tumor-immune microenvironment (TiME) are important for understanding aspects of cancer progression and potential responses to therapy, spatial locations and relationships of these cells also play a critical role. Emerging single-cell imaging modalities, such as multiplex immunohistochemistry (mIHC), provide phenotypic and functional state information for each cell present in the TiME while maintaining the spatial context of tissue architecture. We performed a quantitative analysis of mIHC images to characterize the cellular composition and spatial organization of human head and neck squamous cell carcinomas (HNSCC) and identified features correlated with patient survival.Methods mIHC is an immunoassay-based imaging platform that evaluates sequentially stained immune lineage epitope-specific antibodies for immunodetection on FFPE tissue sections to phenotype single cells as tumor, stromal (mesenchymal), or one of more than 20 different immune cell lineages, all while maintaining the Cartesian coordinates of each cell.1 2 Matched primary and recurrent HNSCC tumors from nine patients were assayed via mIHC. Using unsupervised hierarchical clustering and principal component analysis, we interrogated the heterogeneity in cellular composition of each tumor section. We further quantified the spatial organization of tumors and identified prognostic tumor and immune cell architectures,3 as well as cellular neighborhoods that clustered together based on similar compositions and physically grouped together to reveal common spatial features across tumors.ResultsRegions from the same tumor and tumors from the same patient clustered together more in their cellular composition than tumors from different patients. We also observed a decrease in the fraction of B cells present in recurrent tumors following therapy for all patients (p=0.024). While common biomarkers for HNSCC, such as CD8+ T cell density and tumor cell abundance were not associated with outcome, the tumor-immune spatial relationship was prognostic. Tissue regions of compartmentalization between immune and tumor cells were associated with higher fractions of αSMA+ stromal cells and had a greater proportion of Ki-67+ lymphocytes present, as compared to mixed regions. Patients with more compartmentalization in their primary tumors demonstrated longer progression free survival than those with more mixing between these cell types (p=0.027).ConclusionsOur results provide insight into the spatial organization of HNSCCs, highlighted by the result that compartmentalization between immune and tumor cells is associated with improved outcomes. This study provides spatial analysis methods and hypotheses that can be used as a framework for analysis of larger cohorts.Ethics ApprovalThis study was approved by Oregon Health and Science University’s IRB (protocol #809 and #3609), and written informed consent was obtained.ReferencesTsujikawa T, et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep 2017;19:203–217.Banik G, et al. High-dimensional multiplexed immunohistochemical characterization of immune contexture in human cancers. Methods Enzymol 2020;635:1–20.Keren L, et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 2018;174:1373–1387.

scholarly journals Single-cell profiling of the human decidual immune microenvironment in patients with recurrent pregnancy loss

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chuang Guo ◽  
Pengfei Cai ◽  
Liying Jin ◽  
Qing Sha ◽  
Qiaoni Yu ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Immune Cell ◽  
Recurrent Miscarriage ◽  
Extravillous Trophoblast ◽  
Cellular Interactions ◽  
Immune Microenvironment ◽  
Immune Cell Subsets

AbstractMaintaining homeostasis of the decidual immune microenvironment at the maternal–fetal interface is essential for placentation and reproductive success. Although distinct decidual immune cell subpopulations have been identified under normal conditions, systematic understanding of the spectrum and heterogeneity of leukocytes under recurrent miscarriage in human deciduas remains unclear. To address this, we profiled the respective transcriptomes of 18,646 primary human decidual immune cells isolated from patients with recurrent pregnancy loss (RPL) and healthy controls at single-cell resolution. We discovered dramatic differential distributions of immune cell subsets in RPL patients compared with the normal decidual immune microenvironment. Furthermore, we found a subset of decidual natural killer (NK) cells that support embryo growth were diminished in proportion due to abnormal NK cell development in RPL patients. We also elucidated the altered cellular interactions between the decidual immune cell subsets in the microenvironment and those of the immune cells with stromal cells and extravillous trophoblast under disease state. These results provided deeper insights into the RPL decidual immune microenvironment disorder that are potentially applicable to improve the diagnosis and therapeutics of this disease.

747 Evaluation of immune microenvironment of primary lung cancer and synchronous liver metastasis with multispectral imaging system

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A795-A795
Author(s):  
Hyeonbin Cho ◽  
Jae-Hwan Kim ◽  
Ji-Hyun Kim
Keyword(s):  
T Cells ◽  
Liver Metastasis ◽  
Multispectral Imaging ◽  
Immune Cell ◽  
Imaging System ◽  
Cytotoxic T Cells ◽  
Primary Lung Cancer ◽  
Helper T Cells ◽  
Synchronous Liver Metastasis ◽  
Immune Microenvironment

BackgroundCancer immunotherapy (CIT) has substantially improved the survival of cancer patients. However, according to recent studies, liver metastasis was reported to predict worse outcomes for CIT. The main objective of the study is to evaluate the differences in the immune microenvironment (IME) between the primary lung cancer (PL) and synchronous liver metastasis (LM) using a multispectral imaging system.MethodsSix immune markers (CD4, CD8, CTLA-4, granzyme B (GZB), Foxp3 and PD-L1) were analyzed using a multiplex IHC system and inForm program (Akoya) on paired lung-liver samples of 10 patients. Cells were categorized into tumor nest and stroma, and cell counts per unit area were measured for comparison.ResultsThe number of tumor-infiltrating cytotoxic T cells (TIL) in PL (262.5 cells/mm2) was higher than that of LM (113.3 cells/mm2). Additionally, the ratio between the number of TIL and non-TIL was greater in PL (0.31) compared to that of LM (0.26). A similar trend appeared for Helper T cells and regulatory T cells (Treg), as PL consisted of higher numbers of T cells (791.8 Helper T cells/mm2, 195.7 Treg/mm2) than LM (626.3 Helper T cells/mm2, 121.3 Treg/mm2). However, cytotoxic T cells exhibiting GZB+ and CTLA-4- were fewer in PL (140.2 cells/mm2) than in LM (203.3 cells/mm2), and the ratio is 0.69. The mean number of GZB+ TIL in PL (32.5 cells/mm2) was lower than in LM (35.3 cells/mm2), and their proportions among total TIL counts were 0.12 and 0.31, respectively. In PL, GZB+: GZB- ratio is 0.16 while the ratio is 1.91 for LM. A fewer number of TILs exhibiting GZB suggests that PL has lower efficiency in immune response than LM. Another crucial checkpoint receptor that inhibits immune response, CTLA-4, was more prevalent in PL, with CTLA-4+: CTLA-4- ratio in Treg being 0.36 in PL, compared to 0.11 in LM. The tumor proportion score (TPS) of PD-L1 was higher in PL than LM (40.0 vs. 6.6).ConclusionsIn our study, we showed the differences in the numbers of TIL or regulatory T cells and expressions of immune checkpoint receptors (PD-L1, CTLA-4), which significantly influence outcomes for CIT. The study is ongoing to confirm different IME between the PL and LM groups in a larger tumor cohort.ReferencesPeng, Jianhong, et al., Immune Cell Infiltration in the Microenvironment of Liver Oligometastasis from Colorectal Cancer: Intratumoural CD8/CD3 Ratio Is a Valuable Prognostic Index for Patients Undergoing Liver Metastasectomy. Cancers 2019 Dec; 11(12): 1922. https://doi.org/10.3390/cancers11121922Tumeh, Paul C., et al., Liver Metastasis and treatment outcome with Anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 2017 May; 5(5): 417–424. doi: 10.1158/2326-6066.CIR-16-0325Parra, E.R., Immune Cell Profiling in Cancer Using Multiplex Immunofluorescence and Digital Analysis Approaches; Streckfus, C.F., Ed.; IntechOpen: London, UK, 2018; pp. 1–13. doi: 10.5772/intechopen.80380Ribas, A., Hu-Lieskovan, S., What does PD-L1 positive or negative mean?. The Journal of Experimental Medicine 2016;213(13):2835–2840. https://doi.org/10.1084/jem.20161462

scholarly journals Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2169
Author(s):  
Georgia Karpathiou ◽  
Maroa Dridi ◽  
Lila Krebs-Drouot ◽  
François Vassal ◽  
Emmanuel Jouanneau ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Positive Association ◽  
Immunohistochemical Analysis ◽  
Vascular Density ◽  
Immune Microenvironment ◽  
Significant Positive Association ◽  
Sequestosome 1 ◽  
Cell Expression

Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords (n = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.

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