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CD73 expression on cancer-associated fibroblasts of Head and Neck Cancers shapes the immune landscape

头颈癌癌症相关成纤维细胞上的 CD73 表达塑造免疫景观

基本信息

批准号：
9912757
负责人：
YAN CUI
金额：
$ 19.22万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912757
关键词：
5&apos -Nucleotidase Accounting Address Adenosine Affect Alcohols Apoptosis Biodistribution Biological Assay CTLA4 gene Cancer Patient Cell Death Cell physiology Cells Clinical Development Disease Enzymes Exhibits Fibroblasts Flow Cytometry Frequencies Gene Expression Profiling Genetic Genomics Geography Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Heterogeneity Human Human Papillomavirus Hypoxia ITGAM gene Immune Immune Evasion Immune checkpoint inhibitor Immunosuppression Incidence Individual Investigation Malignant Neoplasms Mesenchymal Metabolic Modification Molecular Mutation Myeloid Cells Neoplasm Metastasis Oral cavity Outcome PD-1/PD-L1 PDL1 pathway Patients Pattern Phenotype Population Population Control Public Health Recurrence Regulatory T-Lymphocyte Reporting Research Project Grants Resources Role Shapes Signal Transduction Smoking Specimen Stress Stromal Cells T-Cell Activation T-Lymphocyte Testing Therapeutic Intervention Tissues Tobacco Tumor Tissue base cancer immunotherapy cancer type cell injury cell type comparative effector T cell extracellular immune checkpoint immune checkpoint blockade immune function inhibitor/antagonist insight neoplastic cell patient response response targeted treatment transcriptome tumor tumor microenvironment tumor-immune system interactions

项目摘要

Head and Neck squamous cell carcinomas (HNSCCs) are highly aggressive multi-factorial diseases affecting 600,000 patients worldwide each year. Alcohol, tobacco, and HPV exposure are known causative factors for HNSCCs, but HPV- HNSCCs represent about 80% of the incidence and are associated with poor clinical outcomes, especially those that manifest a mesenchymal phenotype. Despite the major advances of PD-1/PD- L1 and CTLA-4 checkpoint inhibitors in providing curative benefits for some cancer patients, the response rate in HNSCC patients to these checkpoint inhibitors is limited. Besides the high levels of heterogeneity and immune cell plasticity, a highly immunosuppressive tumor microenvironment (TME) is another contributing factor to the poor clinical outcomes of HNSCCs, which underscores the need for defining additional immune checkpoints non- redundant to the PD-1/PD-L1 pathways. CD73 is a major ecto-5'-nucleotidase and a rate limiting enzyme that converts the immune stimulatory ATP to adenosine (ADO), which inhibits T cell activation and induces apoptosis. Thus, CD73 serves as a prevalent immune checkpoint for maintaining immunosuppression. Clinically, high CD73 expression in total HNSCC tissues has been implicated in poor prognoses. Nevertheless the major contributor of CD73 activity in the HNSCC tumor microenvironment (TME) has not been identified and should be addressed by rigorous and comparative examination of each cell type because the observed elevated CD73 expression in total tumor tissues could be a result of either an increase in CD73 levels in one cellular subtype or an increase in the frequency of this cell type. Recently, we observed that cancer-associated fibroblasts (CAFs), the prominent non-hematopoietic stroma in the TME, expressed the highest levels of CD73, whereas CD73 expression was highly variable in other cellular constituents of the HNSCC TME. Furthermore, immune cell plasticity in HNSCCs, including the loss of T cells in the TME, was associated with high CAF abundancy and high CAF-CD73 levels. Given the highly heterogeneous cellular constituents of HNSCCs, we propose that a comprehensive comparative analysis of CD73 expression in different cell types in the context of their relative abundancy and bio-distribution will provide more insight into the major contributor(s) of the total CD73 activity and the effects of CAF abundancy to immune cell plasticity. Using fresh HNSCC specimens and state-of-the-art technical approaches, we will address the crucial questions of whether and how CAF-CD73 modulates immune cell plasticity with two specific aims: (1) to define and correlate the CD73 expression levels on CAFs with immune cell plasticity via FACs and multiplexed IHC; and (2) to demonstrate the plasticity of CAFs and immune cells in the HNSCC TME via transcriptome profiling of purified tumors, CAFs, and TILs from typical HNSCCs and mesenchymal-like HNSCCs, as well as to demonstrate their differential CD73 enzymatic activity and immunosuppressive function. The results of our systemic and comprehensive analyses will allow us to construct an overall immune landscape of HNSCC TME and to provide invaluable information about the dominant contributing population(s) to the CD73 checkpoint.

头颈部鳞状细胞癌（HNSCC）是一种高度侵袭性的多因素疾病，全球每年有60万患者。酒精，烟草和HPV暴露是已知的致病因素， HNSCC，但HPV-HNSCC代表约80%的发病率，并且与不良的临床表现相关。结果，特别是那些表现出间充质表型的结果。尽管PD-1/PD的重大进展- L1和CTLA-4检查点抑制剂在为一些癌症患者提供治疗益处方面，在HNSCC患者中，这些检查点抑制剂是有限的。除了高水平的异质性和免疫性细胞可塑性，高度免疫抑制的肿瘤微环境（TME）是另一个促成因素， HNSCC的临床结果较差，这强调了定义其他免疫检查点的必要性，对于PD-1/PD-L1通路来说是多余的。CD 73是一种主要的胞外-5 '-核苷酸酶和限速酶，将免疫刺激性ATP转化为腺苷（ADO），其抑制T细胞活化并诱导凋亡。因此，CD 73作为维持免疫抑制的普遍免疫检查点。临床上，高CD 73 在总HNSCC组织中的表达与不良预后有关。然而，主要贡献者 HNSCC肿瘤微环境（TME）中的CD 73活性尚未确定，应予以解决通过对每种细胞类型进行严格的比较性检查，因为在细胞中观察到的CD 73表达升高，总肿瘤组织可能是一种细胞亚型中CD 73水平增加的结果，这种细胞的频率。最近，我们观察到癌症相关成纤维细胞（CAFs）， TME中非造血基质表达最高水平的CD 73，而CD 73表达水平最低。在HNSCC TME的其他细胞成分中高度可变。此外，HNSCC中的免疫细胞可塑性，包括TME中T细胞的损失，与高CAF去除率和高CAF-CD 73水平相关。鉴于HNSCCs的高度异质性细胞成分，我们建议进行全面的比较，分析不同细胞类型中的CD 73表达及其相对表达和生物分布将提供更多关于总CD 73活性的主要贡献者和CAF抑制剂的影响的信息。免疫细胞的可塑性使用新鲜的HNSCC标本和最先进的技术方法，我们将解决了CAF-CD 73是否以及如何通过两种特异性调节免疫细胞可塑性的关键问题。目的：（1）通过FACs确定CAFs上CD 73表达水平与免疫细胞可塑性的关系，多重IHC;和（2）通过免疫组化证实HNSCC TME中CAF和免疫细胞的可塑性。来自典型HNSCC和间充质样HNSCC的纯化肿瘤、CAF和TIL的转录组谱分析，以及证明它们的不同的CD 73酶活性和免疫抑制功能。结果我们的系统和全面的分析将使我们能够构建HNSCC的整体免疫景观 TME，并提供有关CD 73检查点主要贡献人群的宝贵信息。