Sustaining a Th17 Phenotype to Prevent Premalignant Lesion Progression to Cancer

维持 Th17 表型以防止癌前病变进展为癌症

• 批准号: 8774217
• 负责人: M. Rita Young
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774217
• 关键词: 4-Nitroquinoline-1-oxide; Afghanistan; Aging; Alcohols; Antigens; Attention; Autologous; Burn injury; Carcinogens; Cells; Conditioned Culture Media; Dendritic Cells; Development; Exhibits; Exposure to; Goals; Gulf War; Head and Neck Squamous Cell Carcinoma; Health; Immune; Immunity; Incidence; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-17; Interleukin-2; Iraq; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Military Personnel; Mus; Patients; Peptides; Phenotype; Population; Populations at Risk; Premalignant; Prevalence; Recruitment Activity; Regulatory T-Lymphocyte; Risk Factors; Role; Smoking; Specificity; T-Lymphocyte; Testing; Tissues; Tobacco; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Translating; Tumor Antigens; Veterans; antitumor effect; base; cytokine; high risk; inhibitor/antagonist; interleukin-23; malignant mouth neoplasm; mouse model; novel strategies; oral lesion; prevent; public health relevance; receptor; tumor

DESCRIPTION (provided by applicant): Premalignant oral lesions have increased levels of Th17 cells, which are replaced with Treg as lesions become head and neck squamous cell carcinomas (HNSCC). This study aims to prevent progression of premalignant lesions to HNSCC by capitalizing on the anti-tumor effects of Th17 cells. The hypothesis of this study is that sustained stimulation of reactivity mediated b IFN-?-expressing Th17 cells in premalignant oral lesions can promote immunological defenses against premalignant lesions and, consequently, prevent HNSCC. The premise of this hypothesis is that Th17 cells can be potent producers of IFN-?, exhibit antigen-specific activity, and recruit dendritic cells and Th1 T-cells. Also, our studies have shown (i) levels of IFN-?-expressing Th17 cells are increased in premalignant lesions, but are replaced with Treg during progression toward HNSCC, (ii) media conditioned by HNSCC skews the Th17 phenotype of cells from mice with premalignant lesions to a Treg phenotype, but IL-23 lessens the loss of Th17 cells, while neutralization of TGF? prevents development of Treg, (iii) inhibition of inflammation exacerbates lesion development. Our hypothesis will be tested in a carcinogen-induced mouse model in which premalignant oral lesions progress into HNSCC. In addition, studies will transition to assessing reactivity of Th17 cells from patients having premalignant oral lesions against autologous lesions. The following aims will test if sustaining the Th17 phenotype can result in protective immune activity against progression of premalignant lesions to HNSCC: 1. To sustain the Th17- IFN-? + cell phenotype as premalignant oral lesions progress toward HNSCC so as to stimulate lesion-specific immune reactivity and reduce progression to malignancy. a. Determine if sustaining the Th17 phenotype by stabilizing Th17 cells with IL-23 and/or preventing skewing toward Treg cells with a TGF-? receptor inhibitor sustains levels of IFN-? -producing Th17 cells with specificity toward premalignant lesions and HNSCC. b. Determine if stabilizing the Th17- IFN-? + phenotype stimulates immune infiltration that is reactive toward premalignant lesions and against the development of HNSCC. 2. To determine the extent to which Th17 cells from patients bearing premalignant oral lesions exhibit specificity toward autologous lesions and whether this activity can be further stimulated with peptides derived from tumor antigens that are prominently expressed on premalignant lesions and HNSCC. The proposed studies are expected to show that the Th17+ IFN-? + phenotype can promote protective immunity against premalignant oral lesions. Since a high proportion of premalignant oral lesions progress to HNSCC, protective immunity against lesions is expected to translate into reduced development of HNSCC.

描述（由申请人提供）： 口腔癌前病变的 Th17 细胞水平升高，当病变发展为头颈鳞状细胞癌 (HNSCC) 时，Th17 细胞会被 Treg 细胞取代。本研究旨在通过利用 Th17 细胞的抗肿瘤作用来预防癌前病变进展为 HNSCC。本研究的假设是，持续刺激口腔癌前病变中表达 β IFN-γ 的 Th17 细胞的反应性，可以促进针对癌前病变的免疫防御，从而预防 HNSCC。 该假设的前提是 Th17 细胞可以有效产生 IFN-α，表现出抗原特异性活性， 并招募树突状细胞和 Th1 T 细胞。此外，我们的研究还表明（i）癌前病变中表达 IFN-α 的 Th17 细胞水平增加，但在进展为 HNSCC 的过程中被 Treg 取代，（ii）HNSCC 条件培养基使癌前病变小鼠的细胞 Th17 表型偏向 Treg 表型，但 IL-23 减少了 Th17 细胞的损失，同时中和了 TGF?阻止 Treg 的发育，(iii) 抑制炎症会加剧病变的发展。 我们的假设将在致癌物诱导的小鼠模型中得到检验，在该模型中，癌前口腔病变进展为 HNSCC。此外，研究将转向评估患有癌前口腔病变的患者的 Th17 细胞对自体病变的反应性。以下目标将测试维持 Th17 表型是否能够产生保护性免疫活性，防止癌前病变进展为 HNSCC： 1. 维持 Th17-IFN-？ + 口腔癌前病变发展为 HNSCC 时的细胞表型，从而刺激病变特异性免疫反应性并减少恶变进展。 一个。确定是否通过使用 IL-23 稳定 Th17 细胞和/或使用 TGF-β 防止向 Treg 细胞倾斜来维持 Th17 表型？受体抑制剂维持 IFN-α 水平-产生对癌前病变和 HNSCC 具有特异性的 Th17 细胞。 b.确定Th17-IFN-是否稳定？ + 表型刺激免疫浸润，对癌前病变和 HNSCC 的发展有反应。 2. 确定患有口腔癌前病变的患者的 Th17 细胞对自体病变表现出特异性的程度，以及是否可以用源自在癌前病变和 HNSCC 上显着表达的肿瘤抗原的肽进一步刺激这种活性。 拟议的研究预计将表明 Th17+ IFN-？ + 表型可以促进针对癌前口腔病变的保护性免疫。由于大部分癌前口腔病变进展为 HNSCC，因此针对病变的保护性免疫预计会转化为减少 HNSCC 的发展。