Sustaining a Th17 Phenotype to Prevent Premalignant Lesion Progression to Cancer

描述(由申请人提供)： 口腔癌前病变中Th17细胞水平升高，随着病变成为头颈部鳞状细胞癌(HNSCC)，Th17细胞被Treg取代。这项研究旨在通过利用Th17细胞的抗肿瘤作用来防止癌前病变向HNSCC的进展。本研究的假设是，在口腔癌前病变中持续刺激反应性介导的表达干扰素β的Th17细胞可以促进对癌前病变的免疫防御，从而预防HNSCC。这一假设的前提是Th17细胞可以有效地产生干扰素-β，表现出抗原特异性的活性， 并招募树突状细胞和Th1T细胞。我们的研究还表明：(1)表达干扰素的Th17细胞在癌前病变中增加，但在向HNSCC进展过程中被Treg取代；(Ii)HNSCC条件培养液使癌前病变小鼠细胞的Th17表型向Treg表型倾斜，但IL-23减少了Th17细胞的损失，而中和TGF？阻止Treg的发展；(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验证，在该模型中，癌前口腔病变进展为HNSCC。此外，研究将过渡到评估患有口腔癌前病变的患者的Th17细胞对自体病变的反应性。以下目的将测试维持Th17表型是否可以导致保护性免疫活性，以防止癌前病变向HNSCC的进展：1.随着口腔癌前病变向HNSCC的进展，维持Th17-IFN-？+细胞表型，以刺激病变特异性免疫反应，减少向恶性进展。A.确定是否通过用IL-23稳定Th17细胞和/或用转化生长因子阻止Treg细胞向Treg细胞倾斜来维持Th17表型？受体抑制剂维持产生干扰素的Th17细胞的水平，对癌前病变和HNSCC具有特异性。B.确定稳定Th17-干扰素？+表型是否刺激免疫渗透，从而对癌前病变和HNSCC的发展起反应。2.确定口腔癌前病变患者Th17细胞对自身病变的特异性程度，以及癌前病变和HNSCC上显著表达的肿瘤抗原多肽能否进一步刺激这一活性。这些研究有望证明Th17+干扰素？+表型可以促进对口腔癌前病变的保护性免疫。由于很高比例的癌前口腔病变进展为HNSCC，针对病变的保护性免疫预计将转化为HNSCC的减少发展。

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.