scholarly journals Damage-associated molecular patterns and Toll-like receptors in the tumor immune microenvironment

2021 ◽  
Author(s):  
Hideyuki Yanai ◽  
Sho Hangai ◽  
Tadatsugu Taniguchi
Keyword(s):  
Tumor Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Toll Like Receptors ◽  
Immune Microenvironment ◽  
System A ◽  
Molecular Pattern ◽  
Tumor Immune Microenvironment ◽  
Molecular Patterns

Abstract As clinically demonstrated by the success of immunotherapies to improve survival outcomes, tumors are known to gain a survival advantage by circumventing immune surveillance. A defining feature of this is the creation and maintenance of a tumor immune microenvironment (TIME) that directly and indirectly alters the host’s immunologic signaling pathways through a variety of mechanisms. Tumor-intrinsic mechanisms that instruct the formation and maintenance of the TIME have been an area of intensive study, such as the identification and characterization of soluble factors actively and passively released by tumor cells that modulate immune cell function. In particular, damage-associated molecular pattern molecules (DAMPs) typically released by necrotic tumor cells are recognized by innate immune receptors such as Toll-like receptors (TLRs) and stimulate immune cells within TIME. Given their broad and potent effects on the immune system, a better understanding for how DAMP and TLR interactions sculpt the TIME to favor tumor growth would identify new strategies and approaches for cancer immunotherapy.

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 P02.03 Automated cell type specific PD-L1 quantification by artificial intelligence using high throughput bleach & stain 15-marker multiplex fluorescence immunohistochemistry in human cancers

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A8.2-A9
Author(s):  
NC Blessin ◽  
E Bady ◽  
T Mandelkow ◽  
C Yang ◽  
J Raedler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
T Cell Subsets ◽  
Immune Microenvironment ◽  
L1 Data ◽  
Tumor Immune Microenvironment ◽  
Immune Phenotypes ◽  
Fluorescence Immunohistochemistry ◽  
Tumor Entities

BackgroundThe quantification of PD-L1 (programmed cell death ligand 1) has been used to predict patient’s survival, to characterize the tumor immune microenvironment, and to predict response to immune checkpoint therapies. However, a framework to assess the PD-L1 status with a high interobserver reproducibility on tumor cells and different types of immune cells has yet to be established.Materials and MethodsTo study the impact of PD-L1 expression on the tumor immune microenvironment and patient outcome, a framework for fully automated PD-L1 quantification on tumor cells and immune cells was established and validated. Automated PD-L1 quantification was facilitated by incorporating three different deep learning steps for the analysis of more than 80 different neoplasms from more than 10’000 tumor specimens using a bleach & stain 15-marker multiplex fluorescence immunohistochemistry panel (i.e., PD-L1, PD-1, CTLA-4, panCK, CD68, CD163, CD11c, iNOS, CD3, CD8, CD4, FOXP3, CD20, Ki67, CD31). Clinicopathological parameter were available for more than 30 tumor entities and overall survival data were available for 1517 breast cancer specimens.ResultsComparing the automated deep-learning based PD-L1 quantification with conventional brightfield PD-L1 data revealed a high concordance in tumor cells (p<0.0001) as well as immune cells (p<0.0001) and an accuracy of the automated PD-L1 quantification ranging from 90% to 95.2%. Across all tumor entities, the PD-L1 expression level was significantly higher in distinct macrophage/dendritic cell (DC) subsets (identified by CD68, CD163, CD11c, iNOS; p<000.1) and in macrophages/DCs located in the Stroma (p<0.0001) as compared to intratumoral macrophages/DC subsets. Across all different tumor entities, the PD-L1 expression was highly variable and distinct PD-L1 driven immune phenotypes were identified based on the PD-L1 intensity on both tumor and immune cells, the distance between non-exhausted T-cell subsets (i.e. PD-1 and CTLA-4 expression on CD3+CD8+ cytotoxic T-cells, CD3+CD4+ T-helper cells, CD3+CD4+FOXP3+ regulatory T-cells) and tumor cells as well as macrophage/(DC) subtypes. In breast cancer, the PD-L1 fluorescence intensity on tumor cells showed a significantly higher predictive performance for overall survival with an area under receiver operating curves (AUC) of 0.72 (p<0.0001) than the percentage of PD-L1+ tumor cells (AUC: 0.54). In PD-L1 positive as well as negative breast cancers a close spatial relationship between T- cell subsets (CD3+CD4±CD8±FOXP3±PD-1±CTLA-4±) and Macrophage/DC subsets (CD68±CD163±CD11c±iNOS) was found prognostic relevant (p<0.0001).ConclusionsIn conclusion, multiplex immunofluorescence PD-L1 assessment provides cutoff-free/continuous PD-L1 data which are superior to the conventional percentage of PD-L1+ tumor cells and of high prognostic relevance. The combined analysis of spatial PD-L1/PD-1 data and more than 20 different immune cell subtypes of the immune tumor microenvironment revealed distinct PD-L1 immune phenotypes.Disclosure InformationN.C. Blessin: None. E. Bady: None. T. Mandelkow: None. C. Yang: None. J. Raedler: None. R. Simon: None. C. Fraune: None. M. Lennartz: None. S. Minner: None. E. Burandt: None. D. Höflmayer: None. G. Sauter: None. S.A. Weidemann: None.

scholarly journals RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Lan-Xin Mu ◽  
You-Cheng Shao ◽  
Lei Wei ◽  
Fang-Fang Chen ◽  
Jing-Wei Zhang
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Risk Model ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Prognostic Impact ◽  
Immune Microenvironment ◽  
Model Based ◽  
Tumor Immune Microenvironment

Purpose: This study aims to reveal the relationship between RNA N6-methyladenosine (m6A) regulators and tumor immune microenvironment (TME) in breast cancer, and to establish a risk model for predicting the occurrence and development of tumors.Patients and methods: In the present study, we respectively downloaded the transcriptome dataset of breast cancer from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database to analyze the mutation characteristics of m6A regulators and their expression profile in different clinicopathological groups. Then we used the weighted correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and cox regression to construct a risk prediction model based on m6A-associated hub genes. In addition, Immune infiltration analysis and gene set enrichment analysis (GSEA) was used to evaluate the immune cell context and the enriched gene sets among the subgroups.Results: Compared with adjacent normal tissue, differentially expressed 24 m6A regulators were identified in breast cancer. According to the expression features of m6A regulators above, we established two subgroups of breast cancer, which were also surprisingly distinguished by the feature of the immune microenvironment. The Model based on modification patterns of m6A regulators could predict the patient’s T stage and evaluate their prognosis. Besides, the low m6aRiskscore group presents an immune-activated phenotype as well as a lower tumor mutation load, and its 5-years survival rate was 90.5%, while that of the high m6ariskscore group was only 74.1%. Finally, the cohort confirmed that age (p &lt; 0.001) and m6aRiskscore (p &lt; 0.001) are both risk factors for breast cancer in the multivariate regression.Conclusion: The m6A regulators play an important role in the regulation of breast tumor immune microenvironment and is helpful to provide guidance for clinical immunotherapy.

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.

Emerging Mechanisms of Immunosuppression in Oral Cancers

2006 ◽  
Vol 85 (12) ◽  
pp. 1061-1073 ◽  
Author(s):  
A. Jewett ◽  
C. Head ◽  
N.A. Cacalano
Keyword(s):  
Oral Cancer ◽  
Immune Responses ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Oral Cancers ◽  
Oral Cancer Patients ◽  
And Function

Mounting effective anti-tumor immune responses against tumors by both the innate and adaptive immune effectors is important for the clearance of tumors. However, accumulated evidence indicates that immune responses that should otherwise suppress or eliminate transformed cells are themselves suppressed by the function of tumor cells in a variety of cancer patients, including those with oral cancers. Signaling abnormalities, spontaneous apoptosis, and reduced proliferation and function of circulating natural killer cells (NK), T-cells, dendritic cells (DC), and tumor-infiltrating lymphocytes (TILs) have been documented previously in oral cancer patients. Several mechanisms have been proposed for the functional deficiencies of tumor-associated immune cells in oral cancer patients. Both soluble factors and contact-mediated immunosuppression by the tumor cells have been implicated in the inhibition of immune cell function and the progression of tumors. More recently, elevated levels and function of key transcription factors in tumor cells, particularly NFκB and STAT3, have been shown to mediate immune suppression in the tumor microenvironment. This review will focus on these emerging mechanisms of immunosuppression in oral cancers.

scholarly journals Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Xing ◽  
Guojing Ruan ◽  
Haiwei Ni ◽  
Hai Qin ◽  
Simiao Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Immune Microenvironment ◽  
Non Coding Rna ◽  
Tumor Immune Microenvironment ◽  
Downstream Gene Expression

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.

scholarly journals Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential

2021 ◽  
Vol 12 ◽  
Author(s):  
Ya-Nan Pi ◽  
Wen-Cai Qi ◽  
Bai-Rong Xia ◽  
Ge Lou ◽  
Wei-Lin Jin
Keyword(s):  
Therapeutic Potential ◽  
Immune Surveillance ◽  
Biological Properties ◽  
Immune Microenvironment ◽  
Protein Coding ◽  
Innate And Adaptive Immunity ◽  
Non Coding Rna ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Microenvironment ◽  
Long Non Coding Rna

Cancer immunotherapy (CIT) is considered a revolutionary advance in the fight against cancer. The complexity of the immune microenvironment determines the success or failure of CIT. Long non-coding RNA (lncRNA) is an extremely versatile molecule that can interact with RNA, DNA, or proteins to promote or inhibit the expression of protein-coding genes. LncRNAs are expressed in many different types of immune cells and regulate both innate and adaptive immunity. Recent studies have shown that the discovery of lncRNAs provides a novel perspective for studying the regulation of the tumor immune microenvironment (TIME). Tumor cells and the associated microenvironment can change to escape recognition and elimination by the immune system. LncRNA induces the formation of an immunosuppressive microenvironment through related pathways, thereby controlling the escape of tumors from immune surveillance and promoting the development of metastasis and drug resistance. Using lncRNA as a therapeutic target provides a strategy for studying and improving the efficacy of immunotherapy.

scholarly journals Hyperion Image Analysis Depicts a Preliminary Landscape of Tumor Immune Microenvironment in OSCC with Lymph Node Metastasis

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Shang Xie ◽  
Xin-Yuan Zhang ◽  
Xiao-Feng Shan ◽  
Vicky Yau ◽  
Jian-Yun Zhang ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Treatment Planning ◽  
Immune Cell ◽  
Imaging System ◽  
Individual Treatment ◽  
Immune Microenvironment ◽  
Node Metastasis ◽  
Tumor Immune Microenvironment ◽  
Formalin Fixed Paraffin Embedded

Background. Oral squamous cell carcinoma (OSCC) constitutes the most common types of oral cancer. Because its prognosis varies significantly, identification of a tumor immune microenvironment could be a critical tool for treatment planning and predicting a more accurate prognosis. This study is aimed at utilizing the Hyperion imaging system to depict a preliminary landscape of the tumor immune microenvironment in OSCC with lymph node metastasis. Methods. We collected neoplasm samples from OSCC patients. Their formalin-fixed, paraffin-embedded (FFPE) tissue sections were obtained and stained utilizing a panel of 26 clinically relevant metal-conjugated antibodies. Detection and analysis were performed for these stained cells with the Hyperion imaging system. Results. Four patients met our inclusion criteria. We depicted a preliminary landscape of their tumor immune microenvironment and identified 25 distinct immune cell subsets from these OSCC patients based on phenotypic similarity. All these patients had decreased expression of CD8+ T cells in tumor specimens. Variety in cell subsets was seen, and more immune activated cells were found in patient A and patient B than those in patient C and patient D. Such differences in tumor immune microenvironments can contribute to forecasting of individual prognoses. Conclusion. The Hyperion imaging system helped to delineate a preliminary and multidimensional landscape of the tumor immune microenvironment in OSCC with lymph node metastasis and provided insights into the influence of the immune microenvironment in determination of prognoses. These results reveal possible contributory factors behind different prognoses of OSCC patients with lymph node metastasis and provide reference for individual treatment planning.

scholarly journals Interactions between tumor-derived proteins and Toll-like receptors

2020 ◽  
Vol 52 (12) ◽  
pp. 1926-1935
Author(s):  
Gun-Young Jang ◽  
Ji won Lee ◽  
Young Seob Kim ◽  
Sung Eun Lee ◽  
Hee Dong Han ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Tissue Injury ◽  
Suppressor Cells ◽  
Toll Like Receptors ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Dying Cells

AbstractDamage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment.

scholarly journals Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer

2019 ◽  
Vol 20 (4) ◽  
pp. 890 ◽  
Author(s):  
Marco Greppi ◽  
Giovanna Tabellini ◽  
Ornella Patrizi ◽  
Simona Candiani ◽  
Andrea Decensi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Host Cells ◽  
Platinum Based Chemotherapy ◽  
Immunosuppressive Tumor Microenvironment

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Epithelial ovarian cancer (EOC), the most lethal of all gynecological malignancies, is characterized by a unique TME that paves the way to the formation of metastasis and mediates therapy resistance through the deregulation of immune surveillance. A characteristic feature of the ovarian cancer TME is the ascites/peritoneal fluid, a malignancy-associated effusion occurring at more advanced stages, which enables the peritoneal dissemination of tumor cells and the formation of metastasis. The standard therapy for EOC involves a combination of debulking surgery and platinum-based chemotherapy. However, most patients experience disease recurrence. New therapeutic strategies are needed to improve the prognosis of patients with advanced EOC. Harnessing the body’s natural immune defenses against cancer in the form of immunotherapy is emerging as an innovative treatment strategy. NK cells have attracted attention as a promising cancer immunotherapeutic target due to their ability to kill malignant cells and avoid healthy cells. Here, we will discuss the recent advances in the clinical application of NK cell immunotherapy in EOC.

Sign in / Sign up

Export Citation Format

Share Document