Potential involvement of neutrophils in human thyroid cancer

Galdiero, Maria Rosaria; Varricchi, Gilda; Loffredo, Stefania; Bellevicine, Claudio; Lansione, Tiziana; Ferrara, Anne Lise; Iannone, Raffaella; Somma, Sarah Di; Borriello, Francesco; Clery, Eduardo; Triassi, Maria; Troncone, Giancarlo; Marone, Gianni

doi:10.1371/journal.pone.0199740

Cited by 66 publications

(69 citation statements)

References 89 publications

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“…The proportion of immune cells in the TME is also favoring tumor-promoting immune cells. The elevation of TAMs, DCs, MCs, neutrophils, NK cells, and Tregs in PTC has been reported [31][32][33][34][35][36][37][38][39][40]. Our study found that these tumor-promoting immune cells were recruited in large numbers in PTC and exhibited a tumorpromoting immune microenvironment phenotype.…”

Section: Discussionsupporting

confidence: 73%

Immune cell confrontation in the papillary thyroid carcinoma microenvironment

Xie

et al. 2020

Preprint

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Background Papillary thyroid carcinoma (PTC) is classified as an inflammation-driven cancer. A systematic understanding of immune cell infiltration in PTC is essential for subsequent immune research and new diagnostic and therapeutic strategies. Methods Three different algorithms, single-sample gene set enrichment analysis (ssGSEA), immune cell marker and CIBERSORT, were used to evaluate the immune cell infiltration levels (abundance and proportion) in 10 data sets (The Cancer Genome Atlas [TCGA], GSE3467, GSE3678, GSE5364, GSE27155, GSE33630, GSE50901, GSE53157, GSE58545, and GSE60542; a total of 799 PTC and 194 normal thyroid samples). Consensus unsupervised clustering divided PTC patients into low-immunity and high-immunity groups. Weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to analyze the potential mechanisms that cause differences in the immune response. Results Compared with normal tissues, PTC tissues had a higher overall immune level, and the M2 macrophages, Tregs, monocytes, neutrophils, dendritic cells (DCs), mast cells (MCs), and M0 macrophages had higher abundances and proportions in PTC tissues. Compared with early PTC, advanced PTC had higher immune infiltration, and M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages had higher abundances and proportions in advanced PTC. Compared to the low-immunity group patients, the high-immunity group patients presented with a more advanced stage, a larger tumor size, greater lymph node metastasis, higher tall-cell PTC, lower follicular PTC proportions, more BRAF mutations and fewer RAS mutations. Epstein-Barr virus (EBV) infection was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for key module genes. Conclusions In human PTC, M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages played a tumor-promoting role, while M1 macrophages, CD8 + T cells, B cells, NK cells, and T follicular helper (TFH) cells (including eosinophils, γδ T cells, and Th17 cells, with weak supporting evidence) played an antitumor role. During the occurrence and development of PTC, the overall immune level was increased, and the abundance and proportion of tumor-promoting immune cells were significantly increased, indicating that immune escape had aggravated. Finally, we speculate that EBV may play an important role in changing the immune microenvironment of PTC tumors.

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Section: Discussionsupporting

confidence: 73%

Immune cell confrontation in the papillary thyroid carcinoma microenvironment

Xie

et al. 2020

Preprint

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“…One potential mechanism of T cell exclusion is the interaction of LAG3 and GAL3. Studies have shown that the interaction between LAG3 and GAL3 in the tumor microenvironment leads to T cell suppression (Kouo et al 2015) and that the recruitment of T cells may be decreased in GAL3-high tumors (Gordon-Alonso et al 2017). In assessing the immune signatures of DC low and high tumors, we find that the LGALS3/LAG3 ratio is significantly higher in activated DC high tumors, suggesting that this may be a potential mechanism for the immune exclusion environment.…”

Section: Figurementioning

confidence: 64%

“…Finally, neutrophils have been shown to be important for metastasis in multiple cancer types, including melanoma (Soler-Cardona et al 2018), breast cancer (Wculek & Malanchi 2015) and gastric cancer (Hiramatsu et al 2018). Recent literature also suggests involvement of neutrophils Endocrine-Related Cancer in the growth of thyroid carcinomas (Galdiero et al 2018). While the mechanism of neutrophil-mediated enhancement of metastasis is unclear, some studies suggest that neutrophils inhibit CD8 T cells and may attract metastatic cells to new sites (Coffelt et al 2015, Wculek & Malanchi 2015.…”

Section: Discussionmentioning

confidence: 99%

Papillary thyroid carcinoma behavior: clues in the tumor microenvironment

Bergdorf

Ferguson

Mehrad

et al. 2019

Endocrine-Related Cancer

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The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4–4.5, P = 5.4 × 10−4). Increased dendritic cells (OR = 3.4, CI = 1.9–6.3, P = 5.5 × 10−5) and neutrophils (OR = 10.5, CI = 2.7–44, P = 8.7 × 10−4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6–13, P = 4.9 × 10−3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10−3, CI = 5.3 × 10−5–0.031, P = 4.1 × 10−5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.

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“…(13). As well as thyrocytes, these models have been developed to include co-culture with immune cells such as macrophages (14) and neutrophils (15).…”

Section: Figure 4 | (A)mentioning

confidence: 99%

“…The oxygen and nutrient diffusion gradient present within a spheroid structure can promote migration and invasion through changes in gene expression-not present in 2D culture models. The effect of co-cultured cells such as macrophages on migration and invasion of thyroid cancer cells has also been explored as these immune cells have roles in epithelial-mesenchymal transition and subsequent tumor progression (14,15). These assays are also applied in research studies testing the cytotoxic effects of chemotherapy agents.…”

Section: Genetics and Epigeneticsmentioning

confidence: 99%

The Changing Face of in vitro Culture Models for Thyroid Cancer Research: A Systematic Literature Review

et al. 2020

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Background: Thyroid cancer is the most common endocrine malignancy worldwide. Primary treatment with surgery and radioactive iodine is usually successful, however, there remains a small proportion of thyroid cancers that are resistant to these treatments, and often represent aggressive forms of the disease. Since the 1950s, in vitro thyroid culture systems have been used in thyroid cancer research. In vitro culture models have evolved from 2-dimensional thyrocyte monolayers into physiologically functional 3-dimensional organoids. Recently, research groups have utilized in vitro thyroid cancer models to identify numerous genetic and epigenetic factors that are involved with tumorigenesis as well as test the efficacy of cytotoxic drugs on thyroid cancer cells and identify cancer stem cells within thyroid tumors. Objective of Review: The objective of this literature review is to summarize how thyroid in vitro culture models have evolved and highlight how in vitro models have been fundamental to thyroid cancer research. Type of Review: Systematic literature review. Search Strategy: The National Institute for Health and Care Excellence (NICE) Healthcare and Databases Advanced Search (HDAS) tool was used to search EMBASE, Medline and PubMed databases. The following terms were included in the search: "in vitro" AND "thyroid cancer". The search period was confined from January 2008 until June 2019. A manual search of the references of review articles and other key articles was also performed using Google Scholar. Evaluation Method: All experimental studies and review articles that explicitly mentioned the use of in vitro models for thyroid cancer research in the title and/or abstract were considered. Full-text versions of all selected articles were evaluated. Experimental studies were reviewed and grouped according to topic: genetics/epigenetics, drug testing/cancer treatment, and side populations (SP)/tumor microenvironment (TME). Results: Three thousand three hundred and seventy three articles were identified through database and manual searches. One thousand two hundred and sixteen articles remained after duplicates were removed. Five hundred and eighty nine articles were excluded based on title and/or abstract. Of the remaining 627 full-text articles: Chew et al. Thyroid Cancer in vitro Models 24 were review articles, 332 related to genetic/epigenetics, 240 related to drug testing/treatments, and 31 related to SP/TME. Conclusion: In vitro cell culture models have been fundamental in thyroid cancer research. There have been many advances in culture techniques-developing complex cellular architecture that more closely resemble tumors in vivo. Genetic and epigenetic factors that have been identified using in vitro culture models can be used as targets for novel drug therapies. In the future, in vitro systems will facilitate personalized medicine, offering bespoke treatments to patients.

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Potential involvement of neutrophils in human thyroid cancer

Cited by 66 publications

References 89 publications

Immune cell confrontation in the papillary thyroid carcinoma microenvironment

Immune cell confrontation in the papillary thyroid carcinoma microenvironment

Papillary thyroid carcinoma behavior: clues in the tumor microenvironment

The Changing Face of in vitro Culture Models for Thyroid Cancer Research: A Systematic Literature Review

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