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Immune Dysregulation by Human Papillomavirus during Head and Neck Cancer Progression

头颈癌进展过程中人乳头瘤病毒引起的免疫失调

基本信息

批准号：
9321289
负责人：
Dohun Pyeon
金额：
$ 52.5万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321289
关键词：
Adoptive Transfer Antibodies Binding Biological Assay CD8-Positive T-Lymphocytes CD8B1 gene CXCL1 gene CXCL14 gene CXCL2 gene Cancer Etiology Cell Line Cells Cisplatin Clinical Collaborations Color Combined Modality Therapy Development Disease Progression Down-Regulation Epidemic Flow Cytometry Genetic Transcription Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Health Human Human Engineering Human Papillomavirus Human papillomavirus 16 Hypermethylation IL8 gene IL8RB gene Immune Immune response Immunity Immunocompetent Immunodeficient Mouse Immunologist Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Incidence Infiltration Link Malignant Epithelial Cell Malignant Neoplasms Mediating Methods Methylation Modeling Morbidity - disease rate Mus Myelogenous Natural Killer Cells Neoplasm Metastasis Nodal Normal tissue morphology Oncoproteins Oral Oropharyngeal Squamous Cell Carcinoma Outcome Patients Population Progression-Free Survivals Radiation Rag1 Mouse Relapse Reporter Research Sampling Scientist Severity of illness Signal Transduction Specimen Suppressor-Effector T-Lymphocytes Surgeon Testing Therapeutic Tissues Transplantation Tumor Immunity Tumor Suppression Tumor Tissue Tumor stage Validation base cancer cell cancer immunotherapy care systems cell motility cell transformation chemokine chemoradiation genetically modified cells head and neck cancer patient in vivo inhibitor/antagonist keratinocyte lymph nodes mouse model mutant neoplastic cell novel novel therapeutics pathogen prognostic prognostic tool promoter response restoration social tool tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Human papillomaviruses (HPVs) are highly prevalent pathogens causally associated with over 5% of all human cancers, including ~25% of head and neck squamous cell carcinoma (HNSCC). The incidence of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) has increased steeply in the last two decades, and will likely comprise the majority of all HNSCCs in the US and worldwide by 2020. With current therapies, patients must deal with the profound sequelae of treatment, which requires considerable support from health and social care systems. Therefore, novel therapies that decrease morbidity and increase cure rates are essential for patients with HPV-positive HNSCC (HPV+ HNSCC). To develop successful patient therapies for HNSCC, an in-depth understanding of how HPV suppresses the host immune response is urgently needed. Our recent studies have revealed that, while the proinflammatory chemokines are upregulated, a relatively novel chemokine CXCL14 is significantly downregulated in HPV+ HNSCC by the HPV oncoprotein E7-induced CXCL14 promoter hypermethylation. Restoration of CXCL14 expression in HPV+ mouse HNSCC cells suppresses tumor growth in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Mice with CXCL14 expression showed dramatically increased CD8+ T and natural killer (NK) cell populations in tumor tissues and tumor draining lymph nodes, and decreased immunosuppressive immune cells including myeloid- derived suppressor cells (MDSCs). Thus, we hypothesize that CXCL14 downregulation by HPV E7 drives HNSCC development by inducing MDSC infiltration into the TME and failing to elicit CD8+ T and NK cell responses; and that CXCL14 expression and immune cell infiltration in the TME correlate with clinical outcomes of HNSCC patients and boosts tumor suppression in combination with chemoradiation therapy (CRT). This hypothesis will be tested through 4 specific aims: 1) Determine whether CXCL14-induced CD8+ T and NK cells are necessary and sufficient for the antitumor immune response to HNSCC cells, using our immunocompetent syngeneic mouse models transplanted with engineered HPV+ mouse HNSCC cells. 2) Define the mechanisms by which the HPV oncoprotein E7 downregulates CXCL14 expression through promoter hypermethylation, using our promoter methylation reporter assay and HPV16 E7 mutants. 3) Assess the clinical correlation between CXCL14 expression, immune cell infiltration, and clinical outcomes of HNSCC patients, using clinical specimens from HNSCC patients for developing useful prognostic tools. 4) Define if chemoradiation therapy changes HPV E7 and CXCL14 expression in HPV+ HNSCC cells and how CXCL14 re-expression impacts tumor clearance during standard therapies, using in vitro and in vivo chemoradiation therapy in combination with Cxcl14 expression in our our immunocompetent mouse HNSCC model. This proposed study will provide important clues to reactivate antitumor immune responses suppressed by HPV and to develop effective prognostic and therapeutic tools that may be employed in the treatment of HNSCC.

项目概要人乳头瘤病毒 (HPV) 是高度流行的病原体，与超过 5% 的人类感染有因果关系。癌症，包括约 25% 的头颈鳞状细胞癌 (HNSCC)。 HPV 阳性的发生率口咽鳞状细胞癌（OPSCC）在过去二十年中急剧增加，并且将到 2020 年，HNSCC 可能占美国和全球所有 HNSCC 的大部分。采用目前的治疗方法，患者必须处理治疗的深远后遗症，这需要卫生和社会的大力支持护理系统。因此，降低发病率和提高治愈率的新疗法对于 HPV 阳性 HNSCC（HPV+ HNSCC）患者。为了开发成功的 HNSCC 患者疗法，迫切需要深入了解HPV如何抑制宿主免疫反应。我们最近的研究表明，虽然促炎趋化因子上调，但相对 HPV 癌蛋白 E7 诱导的新型趋化因子 CXCL14 在 HPV+ HNSCC 中显着下调 CXCL14启动子高甲基化。 HPV+ 小鼠 HNSCC 细胞中 CXCL14 表达的恢复抑制免疫活性同基因小鼠的肿瘤生长，但不抑制 Rag1 缺陷小鼠的肿瘤生长。小鼠与 CXCL14 表达显示肿瘤中 CD8+ T 和自然杀伤 (NK) 细胞群显着增加组织和肿瘤引流淋巴结，以及免疫抑制性免疫细胞（包括骨髓细胞）减少衍生抑制细胞（MDSC）。因此，我们假设 HPV E7 下调 CXCL14 驱动通过诱导 MDSC 浸润 TME 且未能诱导 CD8+ T 和 NK 细胞而发展为 HNSCC 回应； TME 中 CXCL14 表达和免疫细胞浸润与临床相关 HNSCC 患者的预后并与放化疗联合增强肿瘤抑制治疗（CRT）。该假设将通过 4 个具体目标进行检验：1）确定 CXCL14 是否诱导 CD8+ T 和 NK 细胞对于 HNSCC 细胞的抗肿瘤免疫反应是必要且充分的，使用我们的免疫活性同基因小鼠模型移植了工程化的 HPV+ 小鼠 HNSCC 细胞。 2）定义 HPV 癌蛋白 E7 通过以下方式下调 CXCL14 表达的机制启动子高甲基化，使用我们的启动子甲基化报告基因检测和 HPV16 E7 突变体。 3）评估 CXCL14 表达、免疫细胞浸润和 HNSCC 临床结果之间的临床相关性患者，使用 HNSCC 患者的临床标本来开发有用的预后工具。 4）定义如果放化疗改变 HPV+ HNSCC 细胞中 HPV E7 和 CXCL14 的表达以及 CXCL14 如何改变在使用体外和体内放化疗的标准治疗期间，重新表达会影响肿瘤清除在我们的免疫活性小鼠 HNSCC 模型中结合 Cxcl14 表达进行治疗。这拟议的研究将为重新激活 HPV 抑制的抗肿瘤免疫反应提供重要线索开发可用于治疗 HNSCC 的有效预后和治疗工具。