Reversal of regulatory T cell function in prostate cancer

描述（由申请人提供）：CD4+调节性T （Treg）细胞通过抑制CD4+和CD8+效应细胞反应在自身免疫性疾病中发挥关键作用，但抑制有效的癌症免疫治疗所需的免疫反应。我们最近证实在黑色素瘤和前列腺肿瘤浸润性T细胞中存在抗原特异性CD4+ Treg细胞。这些观察结果可以解释，至少部分解释，为什么用癌症疫苗（包括MHC l类限制性肿瘤抗原或肽）诱导强烈和持久的抗肿瘤反应的尝试在很大程度上是不成功的。本项目的目的是研究Treg细胞在前列腺癌中的存在是否引起免疫抑制和耐受，以及是否可以通过逆转Treg细胞的抑制功能来增强抗肿瘤免疫。申请人实验室的研究已经建立了50多个前列腺肿瘤浸润性T细胞（PTILs）。来自几种PTILs的CD4+和CD8+ Treg细胞均表现出抗原特异性和有效的抑制活性。更重要的是，我们最近证明了黑色素瘤来源的Treg细胞的抑制功能可以被TLR配体特异性逆转。这些初步研究促使我们验证我们的假设，即前列腺癌来源的CD4+和CD8+ Treg细胞的抑制功能可以通过细胞因子和TLR信号调节或逆转。这些独特的前列腺Treg细胞系，加上一些新开发的技术，应该能够识别CD4+和CD8+ Treg细胞的重要配体，从而允许对一个新概念进行更严格的测试——逆转CD4+和/或CD8+ Treg细胞的抑制功能可能会提高癌症免疫治疗的有效性。为了验证我们的新概念和假设，我们提出了三个具体的研究目标：(1)基于表型标记、细胞因子谱和抑制机制表征PTILs的不同亚群；(2)利用已建立的CD4+ Treg细胞系/克隆鉴定这些细胞的配体编码基因，并表征其在调节Treg细胞活化中的作用；(3)剖析Treg细胞的免疫抑制机制和TLR信号对Treg细胞的调节，以获得验证我们的假设所需的关键信息，即逆转CD4+ Treg细胞的抑制功能可以增强体内抗肿瘤免疫。这项为期5年的研究提出的策略将应用于不同人类肿瘤中Treg细胞功能的调节，以验证通过TLR信号或细胞因子改变CD4+ Treg/效应细胞平衡确实有助于更有效的癌症免疫治疗。这些研究的积极成果将为治疗癌症患者，也许还有传染性和自身免疫性疾病开辟新的机会。

DESCRIPTION (provided by applicant): CD4+ regulatory T (Treg) cells play a critical role in autoimmune diseases by suppressing the CD4+ and CD8+ effector cell responses, but inhibit immune responses needed for effective cancer immunotherapy. We recently demonstrated the presence of antigen-specific CD4+ Treg cells in melanoma and prostate tumor-infiltrating T cells. These observations may explain, at least in part, why attempts to elicit strong and durable antitumor responses with cancer vaccines (comprising MHC class l-restricted tumor antigens or peptides) have been largely unsuccessful. The goals of this project are to investigate whether the presence of Treg cells in prostate cancer cause immune suppression and tolerance, and whether antitumor immunity can be enhanced by reversing the suppressive function of Treg cells. Research in the applicant's laboratory has established over 50 prostate tumor infiltrating T cells (PTILs). Both CD4+ and CD8+ Treg cells from several PTILs showed antigen specificity and potent suppressive activity. More importantly, we recently demonstrated that the suppressive function melanoma-derived Treg cells could be specifically reversed by TLR ligands. These preliminary studies prompted us to test our hypothesis that the suppressive function of prostate cancer-derived CD4+ and CD8+ Treg cells could be regulated or reversed by cytokines and TLR signaling. These unique prostate Treg cells lines, together with several newly developed technologies, should enable identification of important ligands for CD4+ and CD8+ Treg cells, permitting in turn more rigorous testing of a novel concept - that reversing the suppressive function of CD4+ and/or CD8+ Treg cells may boost the effectiveness of cancer immunotherapy. To test our novel concept and hypothesis, we propose three specific research aims: (1) characterize different subsets of PTILs on the basis of phenotypic markers, cytokine profiles and suppressive mechanisms; (2) use established CD4+ Treg cell lines/clones to identify genes encoding the ligands of these cells and then characterize their roles in regulating the activation of Treg cells; (3) dissect the immunosuppressive mechanisms and regulation of Treg cells by TLR signaling to gain critical information needed to test our hypothesis that reversing the suppressive function of CD4+ Treg cells would enhance antitumor immunity in vivo. The strategies emerging from this 5-year proposal will be applied to the regulation of Treg cell function in different human tumors to verify that a shift in the CD4+ Treg/effector cell balance through TLR signaling or cytokines is indeed conducive to more effective cancer immunotherapy. A positive outcome of these studies would open new opportunities for treating cancer patients and perhaps infectious and autoimmune diseases as well.