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CD8+CD73+ T cells in the tumor microenvironment of head and neck cancer patients are linked to diminished T cell infiltration and activation in tumor tissue.
头颈部肿瘤患者肿瘤微环境中的 CD8 + CD73 + T 细胞与肿瘤组织中 T 细胞浸润和活化减少有关。
- 影响因子:3.83
- DOI:10.1002/eji.202048626
- 作者列表:"Panigrahi S","Bazdar DA","Albakri M","Ferrari B","Antonelli CJ","Freeman ML","Dubyak G","Zender C","Sieg SF
- 发表时间:2020-06-16
Abstract
:Recent studies have implicated a role for adenosine-dependent immunosuppression in head and neck tumor microenvironments. We describe expression of CD73, an enzyme critical to the generation of adenosine from extracellular AMP, in T cells and other cell types within human head and neck tumors. Flow cytometric analyses of tumor-infiltrating cells indicates that CD3+ cells are the predominant source of CD73 among immune infiltrating cells and that CD73 expression, especially among CD8+ T cells, is inversely related to indices of T cell infiltration and T cell activation in the microenvironment of head and neck tumors. We provide evidence that CD73 expression on peripheral T cells and levels of soluble CD73 in circulation are correlated with CD73 expression on CD8+ T cells in tumors. Moreover, fluorescent microscopy studies reveal that CD8+CD73+ cells are observed in close proximity to tumor cells as well as in surrounding tissue. In vitro studies with peripheral blood T cells indicate that anti-CD3-stimulation causes loss of CD73 expression, especially among cells that undergo proliferation and that exogenous AMP can impair T cell proliferation, while sustaining CD73 expression. These data suggest that CD8+CD73+ T cells may be especially important mediators of immunosuppression in human head and neck cancer. This article is protected by copyright. All rights reserved.
摘要
: 最近的研究表明腺苷依赖性免疫抑制在头颈部肿瘤微环境中的作用。我们描述了人类头颈部肿瘤内 T 细胞和其他细胞类型中 CD73 的表达,CD73 是一种对从细胞外 AMP 生成腺苷至关重要的酶。肿瘤浸润细胞的流式细胞分析表明,CD3 + 细胞是免疫浸润细胞中 CD73 的主要来源,CD73 表达,尤其是 CD8 + T 细胞,与头颈部肿瘤微环境中 T 细胞浸润和 T 细胞活化的指标呈负相关。我们提供的证据表明,外周血 T 细胞上的 CD73 表达和循环中可溶性 CD73 的水平与肿瘤中 CD8 + T 细胞上的 CD73 表达相关。此外,荧光显微镜研究显示,CD8 + CD73 + 细胞与肿瘤细胞以及周围组织非常接近。外周血 T 细胞的体外研究表明,anti-CD3-stimulation 导致 CD73 表达缺失,尤其是在增殖细胞中,外源性 AMP 可损害 T 细胞增殖,同时维持 CD73 表达。这些数据表明,CD8 + CD73 + T 细胞可能是人类头颈癌免疫抑制的特别重要的介质。本文受版权保护。保留所有权利。
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METHODS:INTRODUCTION:Human papillomavirus (HPV) is the most common sexually transmitted infection and is associated with several types of cancer. The number of cases of HPV-associated head and neck squamous cell carcinomas (HNSCCs), especially oropharyngeal carcinomas, has increased significantly in recent years despite decreased tobacco smoking rates. Currently, no data concerning the risk factors and prevalence of HPV in HNSCC patients in all regions of Brazil are available, making it difficult to promote advances in this field of public health. Therefore, our goal is to determine the impact of infection by HPV, including HPVs with different genotypes, on head and neck cancer and the risk factors associated with the development of head and neck cancer in all regions of Brazil. METHODS AND ANALYSIS:This is a case-control study that will include 622 patients and 622 controls from all regions of Brazil. A questionnaire will be applied to gather information on sociodemographic, behavioural and health factors. Oral, cervical or penile/scrotal, and anal specimens and serum samples will be collected from all participants. Formalin-fixed paraffin-embedded tissue from tumour biopsies will be analysed only in the case group. Molecular and serological analyses will be performed to evaluate the presence and role of HPV in the development of head and neck cancer. ETHICS AND DISSEMINATION:This project was approved by the research ethical committee of the proposing institution (Hospital Moinhos de Vento, number 2.852.060). Ethical approval from the collaborators is currently under evaluation and is not yet complete. The results of this study will be presented at meetings with the Brazilian Ministry of Health through technical reports and to the scientific community at national and international events, with subsequent publication of scientific articles.
METHODS:BACKGROUND:Factors related to head and neck cancer and the treatment of the disease can affect quality of life. The aim of this study was to determine factors associated with the severity of impact on oral health-related quality of life (OHRQoL) in survivors of head and neck cancer using a multivariate analysis. METHODS:This cross-sectional study evaluated 90 volunteers who had completed radiotherapy at least 3 months earlier. OHRQoL was assessed using oral health impact profile (OHIP-14) and the data were analyzed using robust variance poisson regression models. RESULTS:The mean total OHIP-14 score was 23.98 ± 12.55. Patients with hyposalivation had 56% higher (worse) mean OHIP-14 total scores (CI:1.11-2.18) and patients with advanced stage tumors had 31% higher mean OHIP-14 total scores (CI:1.03-1.66) in multivariate analyses. CONCLUSION:OHRQoL of survivors of head and neck cancer experienced a negative impact following radiotherapy. The impact was associated with hyposalivation and advanced stage tumors.
METHODS:BACKGROUND:To immunohistochemically evaluate the association between the presence of cancer-associated fibroblasts (CAFs) and the tumour expression of podoplanin (PDPN) in head and neck squamous cell carcinoma (HNSCC) and their association with clinicopathological variables. MATERIAL AND METHODS:A tissue microarray (TMA) with biopsy sections from patients diagnosed with HNSCC was stained with antibodies against the CAFs marker, α-smooth muscle actin (α-SMA), and PDPN. We subsequently evaluated their expression to determine the association between them and with clinicopathological variables including age, primary tumour site, TNM stage, and tumour differentiation grade. RESULTS:Positive reaction to α-SMA was observed in the tumour stroma, revealing spindle-shaped cells compatible with CAFs, which showed a high expression in 62% of cases and a significant association with laryngeal carcinomas, advanced clinical stages, and lower tumour differentiation (P ≤ 0.05). PDPN staining on tumour cells showed low expression in 72% of cases, and it was not associated with any clinicopathological variable or with the presence of CAFs. CONCLUSIONS:The presence of CAFs in the tumour stroma is related to an aggressive phenotype and could increase as the disease progresses, although based on our findings, it would have no relationship, at least directly, with the expression of PDPN.