Commitment and Plasticity of Th17 cells and Tregs in the Tumor Microenvironment

描述（由申请人提供）：最近发现的辅助性T细胞17（Th 17）和调节性T细胞（Treg）显著促进了我们对生理和病理条件下的人类免疫的理解。Th 17细胞具有广泛的免疫抑制能力，并在预防自身免疫和维持免疫稳态中发挥核心作用，而Th 17细胞在宿主防御微生物感染中发挥重要作用，并且是多种炎症和自身免疫性疾病发病机制的重要贡献者。然而，Treg细胞也通过帮助感染性病原体的持续存在和阻断有效的抗肿瘤免疫而具有有害作用。更好地了解Th 17和Treg细胞反应之间的性质和密切联系对于阐明这些细胞在不同疾病发病机制中的作用以及开发治疗和预防免疫相关疾病（包括癌症和自身免疫性疾病）的新策略至关重要。我们最近证明，增加的Th 17细胞群存在于黑色素瘤，卵巢癌，乳腺癌和结肠癌的肿瘤浸润性T细胞（TIL）中。我们进一步发现，人肿瘤浸润性Th 17细胞可以分化为IFN-γ，在多次体外T细胞受体（TCR）刺激和扩增后，产生具有有效抑制活性的FoxP 3+群体，表明肿瘤浸润性Th 17细胞的不稳定性和可塑性。因此，研究Th 17细胞和Treg之间的定型、可塑性和相互转化，了解肿瘤微环境中Th 17细胞向Treg细胞分化的分子机制是非常重要的。我们的长期目标是确定Th 17和Tcl 3在抗肿瘤免疫中的作用，并制定策略来改变它们的相互作用和功能，以改善癌症治疗。该提议的中心假设是Th 17细胞具有发育可塑性，并且可以分化为在肿瘤微环境中具有抑制功能的TcB。具体目标1旨在确定来自非肿瘤部位的Th 17细胞向Treg分化的一般性，然后确定参与Th 17向Treg分化和转化的潜在分子机制，包括FoxP 3表达的表观遗传修饰和谱系特异性转录因子和细胞因子基因的重编程。具体目标2将在小鼠肿瘤模型中研究Th 17细胞在体内分化为T细胞。我们将首先研究肿瘤微环境是否促进B16黑色素瘤肿瘤模型中的Th 17细胞转化为Tcl 3，该模型使用高度纯化的Th 17细胞，该细胞由来自FoxP 3EGFP转基因小鼠的FoxP 3-CD 4 + T细胞极化而成。然后，我们将使用OT-II和FoxP 3EGFP双转基因小鼠来确定抗原刺激是否对Th 17细胞在肿瘤微环境中分化为TcB细胞至关重要。这些研究的积极结果应该会导致新的策略，用于操纵Th 17和Treg细胞定型，用于治疗人类癌症和其他疾病。

DESCRIPTION (provided by applicant): Recent discovery of T-helper 17 (Th17) cells and regulatory T cells (Treg) has markedly facilitated our understanding of human immunity under both physiological and pathological conditions. Tregs have a broad immunosuppressive capacity and play a central role in the prevention of autoimmunity and maintenance of immune homeostasis, whereas Th17 cells play an important role in host defense against microbial infections, and are important contributors to the pathogenesis of a wide array of inflammatory and autoimmune diseases. However, Treg cells also have deleterious effects by aiding the persistence of infectious pathogens and blocking effective anti-tumor immunity. A better understanding of the nature and intimate links between Th17 and Treg cell responses will be critical for the elucidation of the roles of these cells in the pathogenesis of different diseases, and for the development of novel strategies to treat and prevent immune-related diseases including cancer and autoimmune diseases. We recently demonstrated that increased Th17 cell populations exist in the tumor-infiltrating T cells (TILs) of melanoma, ovarian, breast and colon cancers. We further discovered that human tumor-infiltrating Th17 cells can differentiate into IFN-?-producing and FoxP3+ populations possessing potent suppressive activity after multiple in vitro T cell receptor (TCR) stimulations and expansions, suggesting the instability and plasticity of tumor-infiltrating Th17 cells. Therefore, it is critical to investigate the commitment, plasticity and interconversion between Th17 cells and Tregs, and understand the molecular mechanisms responsible for the Th17-to-Treg differentiation in the tumor microenvironment. Our long-term goals are to identify the role of Th17 and Tregs in anti-tumor immunity and develop strategies to modify their interactions and functions for improved cancer treatment. The central hypothesis of this proposal is that Th17 cells have developmental plasticity and can differentiate into Tregs with suppressive function in the tumor microenvironment. Specific Aim 1 seeks to identify the generality of differentiation of Th17 cells derived from non-tumor sites into Tregs, and then to identify the potential molecular mechanisms, including epigenetic modification of FoxP3 expression and reprogramming of lineage-specific transcriptional factor and cytokine genes, involved in the Th17-to-Treg differentiation and conversion. Specific Aim 2 will investigate the differentiation of Th17 cells into Tregs in vivo in mouse tumor models. We will first investigate whether tumor microenvironments promote the conversion of Th17 cells into Tregs in a B16 melanoma tumor model using highly purified Th17 cells polarized from FoxP3-CD4+ T cells derived from FoxP3EGFP transgenic mice. We will then determine whether antigen stimulation is critical for the differentiation of Th17 cells into Tregs in the tumor microenvironment using OT-II and FoxP3EGFP double transgenic mice. A positive outcome of these studies should lead to novel strategies for manipulation of Th17 and Treg cell commitment for the treatment of human cancer and other diseases as well.