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

基本信息

  • 批准号:
    8433545
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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): 癌前口腔病变具有增加的Th 17细胞水平,当病变变成头颈部鳞状细胞癌(HNSCC)时,Th 17细胞被Treg取代。本研究旨在通过利用Th 17细胞的抗肿瘤作用来预防癌前病变进展为HNSCC。本研究的假设是反应性的持续刺激介导了B IFN-?-在癌前口腔病变中表达Th 17细胞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Th 17细胞可以是IFN-β的有效生产者,表现出抗原特异性活性, 并募集树突细胞和Th 1 T细胞。此外,我们的研究表明(i)IFN-γ水平-表达Th 17细胞的癌前病变增加,但在向HNSCC进展过程中被Treg所取代,(ii)HNSCC条件培养基使来自癌前病变小鼠的细胞的Th 17表型偏向Treg表型,但IL-23减少了Th 17细胞的损失,而中和TGF?防止Treg的发展,(iii)抑制炎症加剧病变发展。 我们的假设将在致癌物诱导的小鼠模型中进行测试,其中癌前口腔病变进展为HNSCC。此外,研究将过渡到评估来自具有癌前口腔病变的患者的Th 17细胞对自体病变的反应性。以下目的将测试维持Th 17表型是否可以导致针对癌前病变进展为HNSCC的保护性免疫活性:1.维持Th 17- IFN-?+ 癌前口腔病变向HNSCC进展时的细胞表型,以便 刺激病变特异性免疫反应性并减少恶性进展。 a.确定是否通过用IL-23稳定化Th 17细胞和/或防止Th 17细胞的增殖来维持Th 17表型。 倾向于Treg细胞与TGF-?受体抑制剂维持IFN-?- 产生Th 17细胞 对癌前病变和HNSCC具有特异性。 B.确定是否稳定Th 17- IFN-?+ 表型刺激免疫浸润, 癌前病变和HNSCC的发展。 2.为了确定口腔癌前病变患者的Th 17细胞在多大程度上表现出 对自体病变的特异性以及这种活性是否可以用肽进一步刺激 来源于在癌前病变和HNSCC上显著表达的肿瘤抗原。 拟议的研究预计将表明,Th 17 + IFN-?+ 表型可以促进针对癌前口腔病变的保护性免疫。由于高比例的癌前口腔病变进展为HNSCC,因此预计对病变的保护性免疫将转化为HNSCC的发展减少。

项目成果

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M. Rita Young其他文献

M. Rita Young的其他文献

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{{ truncateString('M. Rita Young', 18)}}的其他基金

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
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
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:
    8624540
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity
维生素 D 加塞来昔布疗法刺激瘤内免疫反应
  • 批准号:
    8586842
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.
免疫疗法可预防口腔永久病变复发和口腔癌。
  • 批准号:
    7754439
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity
维生素 D 加塞来昔布疗法刺激瘤内免疫反应
  • 批准号:
    7910667
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity
维生素 D 加塞来昔布疗法刺激瘤内免疫反应
  • 批准号:
    8195963
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.
免疫疗法可预防口腔永久病变复发和口腔癌。
  • 批准号:
    7574715
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.
免疫疗法可预防口腔永久病变复发和口腔癌。
  • 批准号:
    7928678
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.
免疫疗法可预防口腔永久病变复发和口腔癌。
  • 批准号:
    8010932
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity
维生素 D 加塞来昔布疗法刺激瘤内免疫反应
  • 批准号:
    8390418
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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