Downregulation of AT-rich interaction domain 2 underlies natural killer cell dysfunction in oral squamous cell carcinoma.

The immune system plays a significant role in controlling oral squamous cell carcinoma (OSCC) initiation and progression. Natural killer (NK) cells actively participate in antitumor immunity but become dysfunctional or exhausted in the tumor microenvironment. To explore the mechanisms of NK cell dysfunction in OSCC, we characterized the expression and function of AT-rich interaction domain 2 (ARID2) in NK cells in a murine OSCC model. ARID2 was downregulated in tongue NK cells compared with splenic NK cells. Notably, ARID2 was significantly decreased in NK cells with an exhausted phenotype and weakened antitumor function. ARID2 knockdown resulted in the upregulation of programmed cell death protein 1 (PD-1) and downregulation of interferon-gamma (IFN-γ), tumor necrosis factor (TNF), granzyme B and perforin in NK cells. As a result, ARID2 knockdown impaired NK cell cytotoxicity. Besides, ARID2 overexpression suppressed the expression of PD-1 and lymphocyte-activation gene 3, and promoted the expression of IFN-γ, TNF, granzyme B and perforin in NK cells which were adoptively transferred into OSCC-bearing mice. Taken together, our study implies that the OSCC microenvironment triggers ARID2 downregulation in intratumoral NK cells. In turn, ARID2 downregulation results in PD-1 upregulation on NK cells and subsequently impairs NK cell cytotoxicity. Therefore, we uncovered a novel mechanism of NK cell dysfunction in OSCC.

Interleukin-23 receptor defines T helper 1-like regulatory T cells in oral squamous cell carcinoma.

BACKGROUND: The immune responses play significant roles in the onset, progression, and outcome of oral squamous cell carcinoma (OSCC). CD4+ regulatory T cells (Tregs) significantly impact tumor immunity. However, their role in OSCC development remains elusive. METHODS: In a carcinogen-induced mouse OSCC model, interleukin-23 receptor (IL-23R) expression on Tregs and Treg function were determined by flow cytometry. IL-23R overexpression in Tregs was achieved by lentiviral infection, followed by evaluation of the expression of Forkhead box P3 (Foxp3), T-bet, retineic-acid-receptor-related orphan nuclear receptor gamma t, and cytokines by flow cytometry. Adoptive transfer assays were applied to analyze the function of IL-23R- overexpressing Tregs in vivo. The cellular sources of IL-23 were also determined by flow cytometry. RESULTS: IL-23R- Tregs and IL-23R+ Tregs were found in the tongues but not spleens of OSCC-bearing mice. IL-23R+ Tregs expressed lower Foxp3 but higher T-bet than IL-23R- Tregs. IL-23R- Tregs produced abundant IL-10 and transforming growth factor (TGF)-ß, while IL-23R+ Tregs produced lower IL-10 and TGF-ß but remarkably higher interferon (IFN)-γ. Furthermore, IL-23R+ Tregs possessed more phosphorylated signal transducer and activator of transcription (STAT3) and STAT4 than IL-23R- Tregs. IL-23R+ Tregs were less immunosuppressive than IL-23R- Tregs, as evidenced by weaker inhibition of activated conventional T cells. IL-23R overexpression in splenic Tregs remarkably reduced the expression of IL-10 and TGF-ß but increased IFN-γ expression when Tregs were adoptively transferred into OSCC-bearing mice. In the OSCC microenvironment, macrophages, dendritic cells, and malignant OSCC cells produced IL-23 which might modulate the function of IL-23R+ Tregs. CONCLUSIONS: This study unveils Treg heterogeneity, thus deepening the understanding of Treg biology and tumor immunity in OSCC.

A multifaceted and feasible prognostic model of amino acid metabolism-related genes in the immune response and tumor microenvironment of head and neck squamous cell carcinomas.

We investigated the role of amino acid metabolism (AAM) in head and neck squamous cell carcinoma (HNSCC) tissues to explore its prognostic value and potential therapeutic strategies. A risk score based on four AAM-related genes (AMG) was constructed that could predict the prognosis of HNSCC. These four genes were up-regulated in HNSCC tissues and might act as oncogenes. Internal validation in The Cancer Genome Atlas (TCGA) by bootstrapping showed that patients with high-risk scores had a poorer prognosis than patients with low-risk scores, and this was confirmed in the Gene Expression Omnibus (GEO) cohort. There were also differences between the high-risk and low-risk groups in clinical information and different anatomical sites such as age, sex, TNM stage, grade stage, surgery or no surgery, chemotherapy, radiotherapy, no radiotherapy, neck lymph node dissection or not, and neck lymphovascular invasion, larynx, overlapping lesion of lip, and oral cavity and pharynx tonsil of overall survival (OS). Immune-related characteristics, tumor microenvironment (TME) characteristics, and immunotherapy response were significantly different between high- and low-risk groups. The four AMGs were also found to be associated with the expression of markers of various immune cell subpopulations. Therefore, our comprehensive approach revealed the characterization of AAM in HNSCC to predict prognosis and guide clinical therapy.

Identification of a glioma functional network from gene fitness data using machine learning.

Glioblastoma multiforme (GBM) is an aggressive form of brain tumours that remains incurable despite recent advances in clinical treatments. Previous studies have focused on sub-categorizing patient samples based on clustering various transcriptomic data. While functional genomics data are rapidly accumulating, there exist opportunities to leverage these data to decipher glioma-associated biomarkers. We sought to implement a systematic approach to integrating data from high throughput CRISPR-Cas9 screening studies with machine learning algorithms to infer a glioma functional network. We demonstrated the network significantly enriched various biological pathways and may play roles in glioma tumorigenesis. From densely connected glioma functional modules, we further predicted 12 potential Wnt/ß-catenin signalling pathway targeted genes, including AARSD1, HOXB5, ITGA6, LRRC71, MED19, MED24, METTL11B, SMARCB1, SMARCE1, TAF6L, TENT5A and ZNF281. Cox regression modelling with these targets was significantly associated with glioma overall survival prognosis. Additionally, TRIB2 was identified as a glioma neoplastic cell marker in single-cell RNA-seq of GBM samples. This work establishes novel strategies for constructing functional networks to identify glioma biomarkers for the development of diagnosis and treatment in clinical practice.

The inflammatory cytokine IL-22 promotes murine gliomas via proliferation.

Interleukin (IL)-22 is newly identified proinflammatory cytokine involved in the T helper (Th)17 and Th22 response. However, the possible role of IL-22 in glioma remains uncertain. The results of the present study demonstrated higher expression levels of IL-22 and the receptor IL-22BP in the brain of GL261 glioma-inoculation mice, suggesting the regulatory role of IL-22 in glioma. Injection of IL-22 increased the severity of glioma in vivo and higher expression levels of IL-6, IL-1ß and tumor necrosis factor (TNF)-α were detected in the brain using ELISA following IL-22 injection. To elucidate the mechanism underlying the effects of IL-22, the present study aimed firstly to determine the expression levels of IL-22 receptor in a glioma cell line via reverse transcription quantitative polymerase chain reaction. IL-22 treatment significantly increased the expression levels of signal transducer and activator of transcription (STAT)3 and the mRNA expression levels of STAT6 compared with the vehicle control. These results suggested that IL-22 may activate the Janus kinase (JAK)/STAT signaling pathway in glioma. Furthermore, IL-22 positively regulated the proliferation of glioma, consistent with its role in vivo. Conversely, IL-22-deficient mice exhibited prolonged survival compared with wild-type (WT) mice, and the expression levels of inflammatory cytokines were decreased in the brain of IL-22 knock-out (KO) mice compared with WT mice. Concordant with these results, it was observed that IL-22-neutralising antibody was able to increase the survival of mice with glioma and attenuate the disease by significantly reducing the cytokine levels in the brain. In conclusion, the results of the present study demonstrated that expression levels of IL-22 in the brain of mice with glioma may enhance symptoms due to the increased cytokine production of IL-6, IL-1ß and TNF-α; this is consistent with IL-6/JAK/STAT signalling activation in vitro. Decreasing the expression levels of IL-22, achieved either with IL-22-KO mice or IL-22-neutralising antibody demonstrated protective effects on glioma development. Therefore, IL-22 may serve as a potential therapeutic target for glioma.

Interleukin-22 promotes papillary thyroid cancer cell migration and invasion through microRNA-595/Sox17 axis.

Interleukin-22 (IL-22) is an inflammatory cytokine mainly produced by activated Th17 and Th22 cells. The data presented here demonstrate that IL-22 induced the migration and invasion of papillary thyroid cancer (PTC) cells. MicroRNA expression analysis and functional studies indicated that IL-22-mediated migration and invasion is positively regulated by miR-595. Further mechanistic studies revealed that sex-determining region Y-box 17 (Sox17) is directly targeted by miR-595. We then demonstrated that IL-22 regulated migration and invasion of PTC cells via inhibiting Sox17 expression. Interestingly, in PTC cell lines and PTC tissues, expression of IL-22 and miR-595 was upregulated and Sox17 downregulated compared with normal thyroid, and their expression levels were closely correlated. Taken together, this present study suggests that IL-22 stimulation enhances the migration and invasion of PTC cells by regulating miR-595 and its target Sox17.

[Comparison the application of 3D versus 2D laparoscopic thyroidectomy via modified chest and mammary areola approach].

OBJECTIVE: To explore the safety, effectiveness and feasibility of 3D laparoscopy in thyroidectomy via modified chest and mammary areola approach comparing with 2D. METHOD: Twenty six cases received 3D laparoscopic thyroidectomy (3D group) and 34 cases experienced 2D (2D group). We compared the indexes about general status, operation time, operative blood loss, duration and overall volume of postoperative drainage, complications, etc between two groups. RESULT: Eight cases of thyroid cancer were detected in 3D group and 3 cases in 2D group. While there was no statistical difference between two groups with respect to other observation indexes such as other general status, operation time, operative blood loss, duration and overall volume of postoperative drainage, complications, etc. CONCLUSION: 3D laparoscopic thyroidectomy via modified chest and mammary areola approach is a safe, effective and feasible procedure, and it may substitute the place of 2D in the future.

[122 cases of endoscopic thyroidectomies through modified chest and mammary areola approach].

OBJECTIVE: To explore the safety and feasibility of endoscopic thyroidectomies through modified chest and mammary areola approach. METHOD: We retrospectively analyzed 122 cases of endoscopic thyroidectomies through a modified chest and mammary areola approach without extensive dissection of thoracic flap. The information about general status, surgical procedures and techniques, complications, etc. were summarized and discussed. RESULT: One hundred and twenty-one cases were operated successfully while 1 case was converted to video-assisted thyroidectomy through infraclavicular approach. The maximum diameter of the mass was (2.05 ± 1.06) cm, mean operation time was (88.61 ± 27.87) min, the operative blood loss was (31.23 ± 16.14) ml, duration of postoperative drainage was (3.54 ± 0.88) d and overall drainage volume was (139.09 ± 95.93) ml. Parathyroid glands were detected in specimens of 9 cases while no case of permanent postoperative hypocalcaemia was displayed. 6 cases of hoarseness were developed. One case experienced conversion surgery, all the others obtained satisfactory cosmetic result. All cases were followed up for 0-24 months without relapse and metastasis of the disease. CONCLUSION: Endoscopic thyroidectomy via a modified chest and breast areola approach can facilitated the procedure and avoid extensive dissection of thoracic flap, and proved to be safe and effective.