scholarly journals Immune Landscape of Thyroid Cancers: New Insights

2021 ◽  
Vol 11 ◽  
Author(s):  
Elisa Menicali ◽  
Martina Guzzetti ◽  
Silvia Morelli ◽  
Sonia Moretti ◽  
Efisio Puxeddu
Keyword(s):  
Thyroid Cancer ◽  
Immune System ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Thyroid Tumors ◽  
Thyroid Cancers ◽  
Immune Destruction

Immune system plays a key role in cancer prevention as well as in its initiation and progression. During multistep development of tumors, cells must acquire the capability to evade immune destruction. Both in vitro and in vivo studies showed that thyroid tumor cells can avoid immune response by promoting an immunosuppressive microenvironment. The recruitment of immunosuppressive cells such as TAMs (tumor-associated macrophages), TAMCs (tumor-associated mast cells), MDSC (myeloid-derived suppressor cells), TANs (tumor-associated neutrophils) and Tregs (regulatory T cells) and/or the expression of negative immune checkpoints, like PD-L1 (programmed death-ligand 1), CTLA-4 (cytotoxic T-lymphocyte associated protein 4), and/or immunosuppressive enzymes, as IDO1 (indoleamine 2,3-dioxygenase 1), are just some of the mechanisms that thyroid cancer cells exploit to escape immune destruction. Some authors systematically characterized immune cell populations and soluble mediators (chemokines, cytokines, and angiogenic factors) that constitute thyroid cancer microenvironment. Their purpose was to verify immune system involvement in cancer growth and progression, highlighting the differences in immune infiltrate among tumor histotypes. More recently, some authors have provided a more comprehensive view of the relationships between tumor and immune system involved in thyroid carcinogenesis. The Cancer Genome Atlas (TCGA) delivered a large amount of data that allowed to combine information on the inflammatory microenvironment with gene expression data, genetic and clinical-pathological characteristics, and differentiation degree of papillary thyroid carcinoma (PTC). Moreover, using a new sensitive and highly multiplex analysis, the NanoString Technology, it was possible to divide thyroid tumors in two main clusters based on expression of immune-related genes. Starting from these results, the authors performed an immune phenotype analysis that allowed to classify thyroid cancers in hot, cold, or intermediate depending on immune infiltration patterns of the tumor microenvironment. The aim of this review is to provide a comprehensive and updated view of the knowledge on immune landscape of thyroid tumors. Understanding interactions between tumor and microenvironment is crucial to effectively direct immunotherapeutic approaches in the treatment of thyroid cancer, particularly for those not responsive to conventional therapies.

scholarly journals An integrated framework for quantifying immune-tumour interactions in a 3D co-culture model

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Gheed Al-Hity ◽  
FengWei Yang ◽  
Eduard Campillo-Funollet ◽  
Andrew E. Greenstein ◽  
Hazel Hunt ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
In Vitro Models ◽  
Proof Of Concept ◽  
Culture Model ◽  
Spheroid Growth ◽  
Confocal Images ◽  
Cancer Spheroids

AbstractInvestigational in vitro models that reflect the complexity of the interaction between the immune system and tumours are limited and difficult to establish. Herein, we present a platform to study the tumour-immune interaction using a co-culture between cancer spheroids and activated immune cells. An algorithm was developed for analysis of confocal images of the co-culture to evaluate the following quantitatively; immune cell infiltration, spheroid roundness and spheroid growth. As a proof of concept, the effect of the glucocorticoid stress hormone, cortisol was tested on 66CL4 co-culture model. Results were comparable to 66CL4 syngeneic in vivo mouse model undergoing psychological stress. Furthermore, administration of glucocorticoid receptor antagonists demonstrated the use of this model to determine the effect of treatments on the immune-tumour interplay. In conclusion, we provide a method of quantifying the interaction between the immune system and cancer, which can become a screening tool in immunotherapy design.

scholarly journals Resolvins as Regulators of the Immune System

2010 ◽  
Vol 10 ◽  
pp. 818-831 ◽  
Author(s):  
Hiroyuki Seki ◽  
Takaharu Sasaki ◽  
Tomomi Ueda ◽  
Makoto Arita
Keyword(s):  
Immune System ◽  
Acute Inflammation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Bioactive Metabolites ◽  
Cell Functions ◽  
First Response ◽  
Beneficial Impact

Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of ω-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions bothin vitroandin vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.

Serous BMP8A has Clinical Significance in the Ultrasonic Diagnosis of Thyroid Cancer and Promotes Thyroid Cancer Cell Progression

2020 ◽  
Vol 20 (4) ◽  
pp. 591-598 ◽  
Author(s):  
Kun Liu ◽  
Min Gao ◽  
Dongdong Qin ◽  
Hongjun Wang ◽  
Qixiu Lu
Keyword(s):  
Thyroid Cancer ◽  
Early Diagnosis ◽  
Cell Viability ◽  
Soft Agar ◽  
The Cancer Genome Atlas ◽  
Anchorage Independent Growth ◽  
Over Expression ◽  
Diagnosis Of Thyroid Cancer

Objectives: This study aims to discover a potential cytokine biomarker for early diagnosis of thyroid cancer. Methods: We employed data mining of The Cancer Genome Atlas (TCGA) and experimentally elucidated its mechanistic contributions. The differential expression genes (DEGs) between thyroid cancer and health population were analyzed with TCGA online bioinformatic tools. The relative expression of Bone Morphogenetic Protein 8A (BMP8A) was determined by real-time PCR in ultrasonic diagnosed thyroid cancer both in vivo and in vitro. The serous BMP8A content was quantified with an ELISA kit. Protein levels of BMP8A, OCLN, ZEB1, EZH2 and β-Actin were analyzed by Western blot. Cell viability was measured by the MTT assay, and anchorage-independent growth was measured by the soft agar colony formation assay. Cell migrative and invasive capacities were interrogated with transwell chamber assays. Results: We identified aberrantly high expression of BMP8A in thyroid cancer, which was associated with unfavorable prognosis and tumor progression. The serous BMP8A was also significantly up-regulated in thyroid cancer patients. Ectopic over-expression of BMP8A remarkably stimulated cell viability and anchorage-independent growth. Meanwhile, the migrative and invasive capacities were greatly increased in response to BMP8A over-expression. Mechanistically, we characterized the positive correlation between BMP8A and TCF7L1, and forced expression of TCF7L1 induced BMP8A expression in TPC-1 cells. Conclusion: In summary, we have identified a novel biomarker for early diagnosis in addition to Ultrasound for thyroid cancer, which is subjected to TCF7L1 regulation.

scholarly journals Immune Gene Signature Delineates a Subclass of Papillary Thyroid Cancer with Unfavorable Clinical Outcomes

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 494 ◽  
Author(s):  
Kyuryung Kim ◽  
Sora Jeon ◽  
Tae-Min Kim ◽  
Chan Jung
Keyword(s):  
Clinical Outcomes ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cytolytic Activity ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Immune Gene ◽  
Papillary Thyroid ◽  
Thyroid Cancers

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance.

213 Use of A novel peptide ligand targeting multiple immune checkpoints: a novel approach to immunotherapy against central nervous system tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A232-A232
Author(s):  
Christopher Moertel ◽  
Zhengming Xiong ◽  
Michael Olin
Keyword(s):  
Clinical Trial ◽  
Immune System ◽  
Immune Checkpoint ◽  
Signaling Molecules ◽  
Immune Checkpoints ◽  
Peptide Ligand ◽  
Autologous Tumor ◽  
Open Label

BackgroundCancer immunotherapy has revolutionized clinical management of malignancies by generating long-term, durable control of tumors, rendering more manageable diseases that previously had dismal prognoses. Unfortunately, these therapies often enhance autoimmunity, causing serious immune-related adverse events. In addition, little efficacy is noted in CNS tumors. Our research is focused on the CD200 immune checkpoint, which modulates the immune system through the inhibitory receptor (CD200R1) and activation receptors (CD200AR). We have demonstrated that targeting the CD200AR with a peptide ligand (CD200AR-L) activates the immune system, rendering it impervious to the inhibitory effects of CD200. In a clinical trial studying canine spontaneous high-grade glioma, CD200AR-L administered with tumor autologous tumor lysate resulted in a 20% two-year progression-free survival. No adverse effects were observed. We suggest this result is due to the ability of the CD200AR-L to modulate multiple immune checkpoints. During the characterization of the CD200AR-L, we discovered that signaling molecules are shared by CD200 and PD-1/PD-L1, suggesting these important immune checkpoints are interconnected.MethodsCD200R1KO macrophages were used to determine the connection between the CD200 and PD-1 checkpoints. Next, we analyzed signaling molecules activated in CD11b cells pulsed with PD-L1 ± CD200AR-L, followed up with in vitro and in vivo effects of CD200AR-L on the expression of PD-1/PD-L1 and CTLA-4. Finally, we analyzed the ability of the CD200AR-L to surmount the suppressive effects of PD-L1.ResultsOur studies demonstrate that the inhibitory CD200R1 and PD-1 mediate immune checkpoint signaling activities through SHIP1 protein. Moreover, CD200AR-L overpowers the suppressive effects of CD200 and PD-L1, which are both shed by tumors, by downregulating the inhibitory CD200R1 and PD-1 on both antigen-presenting cells (APC) and T-cells (figure 1), In addition, CD200AR-L downregulates PD-1 on APCs and inhibits the upregulation of PD-L1 and CTLA4.Abstract 213 Figure 1Mechanism of the CD200 Checkpoint LigandConclusionsThese studies led to the discovery that this novel peptide modulates the CD200, PD-1/PD-L1 and CTLA-4 pathways, providing the basis for the translatable development of a novel CD200 peptide inhibitor for clinical use against multiple tumors, including gliomas. These studies led to the FDA approval for the first in human peptide checkpoint inhibitor to initiate a phase I single center, open-label, dose-escalation clinical trial in adult patients with recurrent glioblastoma, to be followed by a clinical trial for children with recurrent malignant brain tumors.

scholarly journals Immune System Dysfunction and Autoimmune Disease in Mice Lacking Emk (Par-1) Protein Kinase

2001 ◽  
Vol 21 (9) ◽  
pp. 3206-3219 ◽  
Author(s):  
Jonathan B. Hurov ◽  
Thaddeus S. Stappenbeck ◽  
Christian M. Zmasek ◽  
Lynn S. White ◽  
Sheila H. Ranganath ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Protein Kinase ◽  
Autoimmune Disease ◽  
Immune Cell ◽  
Interleukin 4 ◽  
Parotid Glands ◽  
Immune System Dysfunction

ABSTRACT Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption.Emk −/− mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4+T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. AsEmk −/− animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.

scholarly journals Long noncoding RNA LINC00284 facilitates cell proliferation in papillary thyroid cancer via impairing miR-3127-5p targeted E2F7 suppression

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Bin Zhou ◽  
Yugang Ge ◽  
Qing Shao ◽  
Liyi Yang ◽  
Xin Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Noncoding Rna ◽  
The Cancer Genome Atlas ◽  
G1 Arrest ◽  
Papillary Thyroid ◽  
Bioinformatics Analyses

AbstractAccumulating evidence has suggested that long noncoding RNAs (lncRNAs) exert crucial modulation roles in the biological behaviors of multiple malignancies. Nonetheless, the specific function of lncRNA LINC00284 in papillary thyroid cancer (PTC) remains not fully understood. The objective of this research was to explore the influence of LINC00284 in PTC and elucidate its potential mechanism. The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO) datasets were used to analyze LINC00284 expression differences in thyroid cancer and normal samples, followed by the verification of qRT-PCR in our own PTC and adjacent non-tumor tissues. The impacts of LINC00284 on PTC cell growth were detected in vitro via CCK-8, colony formation, EdU assays, and in vivo via a xenograft tumor model. Bioinformatics analyses and biological experiments were conducted to illuminate the molecular mechanism. We found that LINC00284 expression was remarkably increased in PTC tissues and its overexpression was closely correlated with larger tumor size. In addition, silencing LINC00284 could effectively attenuate PTC cell proliferation, induce apoptosis and G1 arrest in vitro, as well as suppress tumorigenesis in mouse xenografts. Mechanistic investigations showed that LINC00284 acted as a competing endogenous RNA (ceRNA) for miR-3127-5p, thus resulting in the disinhibition of its endogenous target E2F7. In short, our findings indicated that LINC00284–miR-3127-5p–E2F7 axis exerted oncogenic properties in PTC and may offer a new promising target for the diagnosis and therapy of PTC.

TAMI-12. CANCER-IMMUNE CELL INTERACTIONS DRIVE TRANSITIONS TO MESENCHYMAL-LIKE STATES IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi200-vi200
Author(s):  
Toshiro Hara ◽  
Rony Chanoch-Myers ◽  
Nathan Mathewson ◽  
Chad Myskiw ◽  
Lyla Atta ◽  
...  
Keyword(s):  
Immune Cell ◽  
Oncostatin M ◽  
The Cancer Genome Atlas ◽  
Cellular Interactions ◽  
Glioblastoma Cells ◽  
Deconvolution Analysis ◽  
Cognate Receptor ◽  
Cancer Genome Atlas

Abstract Communication between cancer cells and immune cells is a key determinant of the glioblastoma ecosystem and its response to therapies, but remains poorly understood. Here we leveraged single-cell RNA-sequencing (scRNA-seq) of human samples and mouse models, deconvolution analysis of bulk specimens from The Cancer Genome Atlas (TCGA) and functional approaches to dissect cellular states and cross-talk in glioblastoma. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived Oncostatin M (OSM) and its cognate receptor OSMR on glioblastoma cells. We show that MES-like glioblastoma states are associated with increased T cells cytotoxicity and potentially with better clinical response to immunotherapies. Overall, our work dissects the cellular interactions within the glioblastoma microenvironment, with potential implications for therapies.

scholarly journals Galectin-9/TIM-3 as a Key Regulator of Immune Response in Gliomas With Chromosome 1p/19q Codeletion

2021 ◽  
Vol 12 ◽  
Author(s):  
Guanzhang Li ◽  
Ruoyu Huang ◽  
Wenhua Fan ◽  
Di Wang ◽  
Fan Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Responses ◽  
The Cancer Genome Atlas ◽  
Antitumor Immune Response ◽  
Immune Checkpoints ◽  
Sequencing Data ◽  
Chromosome 1P ◽  
Genome Atlas

Gliomas with chromosome 1p/19q codeletion were considered a specific tumor entity. This study was designed to reveal the biological function alterations tightly associated with 1p/19q codeletion in gliomas. Clinicopathological and RNA sequencing data from glioma patients were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Gene set variation analysis was performed to explore the differences in biological functions between glioma subgroups stratified by 1p/19q codeletion status. The abundance of immune cells in each sample was detected using the CIBERSORT analytical tool. Single-cell sequencing data from public databases were analyzed using the t-distributed stochastic neighbor embedding (t-SNE) algorithm, and the findings were verified by in vitro and in vivo experiments and patient samples.We found that the activation of immune and inflammatory responses was tightly associated with 1p/19q codeletion in gliomas. As the most important transcriptional regulator of Galectin-9 in gliomas, the expression level of CCAAT enhancer-binding protein alpha in samples with 1p/19q codeletion was significantly decreased, which led to the downregulation of the immune checkpoints Galectin-9 and TIM-3. These results were validated in three independent datasets. The t-SNE analysis showed that the loss of chromosome 19q was the main reason for the promotion of the antitumor immune response. IHC protein staining, in vitro and in vivo experiments verified the results of bioinformatics analysis. In gliomas, 1p/19q codeletion can promote the antitumor immune response by downregulating the expression levels of the immune checkpoint TIM-3 and its ligand Galectin-9.

scholarly journals OTME-7. Cancer - immune cell interactions drive transitions to mesenchymal-like state in glioblastoma

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii14-ii15
Author(s):  
Toshiro Hara ◽  
Rony Chanoch-Myers ◽  
Nathan Mathewson ◽  
Chad Myskiw ◽  
Lyla Atta ◽  
...  
Keyword(s):  
Immune Cell ◽  
Oncostatin M ◽  
The Cancer Genome Atlas ◽  
Glioblastoma Cells ◽  
Bulk Specimen ◽  
Deconvolution Analysis ◽  
Therapeutic Implications ◽  
Cancer Genome Atlas

Abstract Communication between cancer cells and immune cells is a key determinant of the glioblastoma ecosystem and its response to therapies, but remains poorly understood. Here we leveraged single-cell RNA-sequencing (scRNA-seq) of human samples and mouse models, deconvolution analysis of bulk specimen from The Cancer Genome Atlas (TCGA) and functional approaches, to dissect cellular cross-talks in glioblastoma. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived Oncostatin M (OSM) and its cognate receptor OSMR on glioblastoma cells. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.

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