Head Neck Cancer, beta-defensins, and immune responses

头颈癌、β-防御素和免疫反应

• 批准号: 9091572
• 负责人: Ge Jin
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091572
• 关键词: Accounting; Advanced Malignant Neoplasm; Animal Model; Automobile Driving; Basal Cell; Biology; CCL2 gene; Carcinoma in Situ; Cells; Cessation of life; Chemical Immunotherapy; Chemotactic Factors; Clinical; Data; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease; Early identification; Epidermal Growth Factor Receptor; Epithelial Cells; Etiology; Evaluation; Feedback; Genes; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; Human; Immune; Immune response; Immunomodulators; Immunotherapeutic agent; In Situ Lesion; In Vitro; Intervention; Lead; Malignant Neoplasms; Mediating; Molecular; Monocyte Chemoattractant Protein-1; Mouth Carcinoma; Mus; Myelogenous; Myeloid Cells; National Institute of Dental and Craniofacial Research; Neoplasm Metastasis; Nodal; Nude Mice; Oral; Oral mucous membrane structure; Orthologous Gene; Pathway interactions; Patients; Pattern; Peptides; Play; Prevention; Protein p53; Proteins; Publishing; Recruitment Activity; Recurrence; Reporting; Research; Risk Assessment; Role; Sampling; Signal Pathway; Signal Transduction; Strategic Planning; Structure-Activity Relationship; Suppressor-Effector T-Lymphocytes; Survival Rate; Testing; Therapeutic; Tissues; Treatment Failure; Tumor Immunity; Tumor Suppression; Tumor stage; Tumorigenicity; United States National Institutes of Health; adaptive immunity; anticancer research; beta-Defensins; beta-defensin 3; carcinogenesis; cell motility; chemokine; chemokine receptor; combat; cytokine; head and neck cancer patient; human subject; improved; in vivo; innovation; macrophage; malignant mouth neoplasm; monocyte; mouse model; mouth squamous cell carcinoma; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; success; therapy resistant; tumor; tumor ablation; tumor growth; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Head and neck cancer (HNC) compromises approximately 3-5% of all malignancies, causing an estimated 50,000 new cases and over 10,000 reported deaths each year in the US. Despite our improved understanding of the etiology and biology at the molecular level and advances in therapeutics, the 5-year survival rate of HNC only improved marginally to about 57%, with tumor recurrence, metastasis, and resistance to therapy as common causes of treatment failure. The long-term goal of this proposed research is to better understand innate and adaptive immune responses to head and neck cancers for the development of effective immunotherapeutic approaches to combat the deadly disease. Our studies have shown that head and neck squamous cell carcinoma overexpresses human beta-defensin 3 (hBD3), correlating with accumulation of tumor-associated macrophages (TAMs) via the chemokine receptor CCR2. The expression of hBD3 is induced by the activation of epidermal growth factor receptor (EGFR) and the Wnt signaling as well as by inactivation of the tumor suppressor p53; all three pathways are implicated in HNC development. In addition, hBD3 stimulates human macrophages to express tumor-promoting chemokines and cytokines, potentially forming a positive feedback loop driving tumor progression. Importantly, our preliminary data show that HNC-derived hBD3 correlates with accumulation of myeloid-derived suppressor cells (MDSCs). Therefore, we hypothesize that HNC-derived hBD3 functions as an immunomodulator to recruit and activate TAMs and MDSCs, which in turn promote progression of tumors and suppression of anti-tumor immunity. This hypothesis will be tested by two specific aims: 1. Delineate the mechanism by which hBD3 promotes HNC progression through recruitment and activation of tumor-promoting myeloid cells. We will identify signaling pathways and structural features of hBD3 in interaction with TAMs and MDSCs and perform clinical analyses to correlate hBD3 expression with immune responses to HNC in patients. 2. Determine the mechanism by which mBD14, the ortholog of hBD3, promotes tumorigenicity associated with increased TAMs and MDSCs in vivo. We will evaluate the effect of mBD14 on HNC progression and immune responses using an orthotopic mouse model, and then determine the effect of CCR2 blockade and TAM and MDSC depletion on HNC progression in vivo. This proposed research may delineate a new research discovery platform for gene/chemical/immunotherapy interrogation, which will potentially lead to new therapeutic options targeting hBD3 signaling. Evaluation of hBD3 in HNC progression animal models and in HNC patients in association with immune responses is entirely novel. This innovative approach will provide us with new information about immune responses to HNC progression.

 描述（由适用提供）：头颈癌（HNC）损害了所有恶性肿瘤的大约3-5％，估计在美国造成50,000例新病例，每年有10,000例死亡死亡。尽管我们在分子水平上对病因和生物学的了解得到了提高，但HNC的5年生存率仅略有提高到约57％，并随着肿瘤复发，转移和对治疗的抗药性，作为治疗失败的常见原因。这项拟议研究的长期目标是更好地理解和适应对头颈癌的免疫治疗反应，以开发有效的免疫治疗方法来抗击致命疾病。我们的研究表明，头颈鳞状细胞癌过表达人β-防御素3（HBD3），与通过趋化因子接收器CCR2的肿瘤相关巨噬细胞（TAM）的积累相关。 HBD3的表达是由表皮生长因子受体（EGFR）和Wnt信号的激活以及通过肿瘤抑制p53的失活而诱导的。所有三个途径均在HNC开发中实施。此外，HBD3刺激人类巨噬细胞表达促肿瘤的趋化因子和细胞因子，可能形成阳性反馈环驱动肿瘤进展。重要的是，我们的初步数据表明，HNC衍生的HBD3与髓样衍生的抑制细胞（MDSC）的积累相关。因此，我们假设HNC衍生的HBD3是募集和激活TAM和MDSC的免疫调节剂，这又促进了肿瘤的进展和抑制抗肿瘤免疫史。该假设将通过两个特定目的进行检验：1。描述HBD3通过募集和激活肿瘤促髓样细胞促进HNC进展的机制。我们将确定HBD3与TAM和MDSC相互作用的信号通路和结构特征，并进行临床分析，以将HBD3表达与患者的HNC相关联。 2。确定MBD14（HBD3的直系同源物）促进与体内TAM和MDSC增加相关的肿瘤性的机制。我们将评估MBD14对HNC进展和免疫回应的影响。使用原位小鼠模型的响应，然后确定CCR2阻断，TAM和MDSC部署对体内HNC进展的影响。这项拟议的研究可能会描述一个新的研究发现平台，用于基因/化学/免疫疗法询问，这可能会导致针对HBD3信号传导的新治疗选择。 HNC进展动物模型和HNC患者中HBD3的评估完全是新颖的。创新的方法将为我们提供有关HNC进展的免疫反应的新信息。