Head Neck Cancer, beta-defensins, and immune responses

头颈癌、β-防御素和免疫反应

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：头颈癌 (HNC) 约占所有恶性肿瘤的 3-5%，尽管我们对其病因学和生物学的了解有所提高，但在美国每年仍导致约 50,000 例新病例和 10,000 多人死亡。从分子水平和治疗方法的进步来看，HNC的5年生存率仅略有提高至57%左右，且肿瘤复发、转移和治疗耐药这项研究的长期目标是更好地了解头颈癌的先天性和适应性免疫反应，以开发有效的免疫治疗方法来对抗这种致命的疾病。颈部鳞状细胞癌过表达人 β-防御素 3 (hBD3)，通过趋化因子受体 CCR2 与肿瘤相关巨噬细胞 (TAM) 的积累相关。hBD3 的表达是由 β-防御素 3 (hBD3) 的激活诱导的。表皮生长因子受体 (EGFR) 和 Wnt 信号传导以及肿瘤抑制因子 p53 的失活；所有三种途径都与 HNC 的发展有关。此外，hBD3 刺激人类巨噬细胞表达促肿瘤趋化因子和细胞因子，从而可能形成促肿瘤趋化因子。重要的是，我们的初步数据表明 HNC 衍生的 hBD3 与骨髓源性抑制细胞 (MDSC) 的积累相关。 HNC 衍生的 hBD3 作为免疫调节剂来招募和激活 TAM 和 MDSC，进而促进肿瘤进展并抑制抗肿瘤免疫。这一假设将通过两个具体目标进行检验： 1. 描述 hBD3 促进的机制。通过招募和激活肿瘤促进骨髓细胞来促进 HNC 进展我们将确定 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 表达与免疫相关联。 2. 确定 hBD3 的直系同源物 mBD14 促进与体内 TAM 和 MDSC 增加相关的致瘤性的机制，我们将使用原位小鼠模型评估 mBD14 对 HNC 进展和免疫反应的影响。然后确定 CCR2 阻断以及 TAM 和 MDSC 消耗对体内 HNC 进展的影响。这项研究可能会为 HNC 的体内进展描绘出一个新的研究发现平台。基因/化学/免疫治疗询问，这可能会导致针对 hBD3 信号传导的新治疗选择。在 HNC 进展动物模型和 HNC 患者中评估 hBD3 与免疫反应的关系是全新的，这种创新方法将为我们提供有关 hBD3 信号的新信息。 HNC 进展的免疫反应。