Reversal of regulatory T cell function in prostate cancer

前列腺癌中调节性 T 细胞功能的逆转

• 批准号: 7658065
• 负责人: Rongfu Wang
• 金额: $ 25.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-07 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658065
• 关键词: Animal Model; Antigens; Antitumor Response; Autoimmune Diseases; Biological Assay; CD8B1 gene; Cancer Etiology; Cancer Patient; Cancer Vaccines; Cell Line; Cell physiology; Cells; Clinical; Clinical Trials; Data; Dendritic Cells; Development; Effectiveness; Effector Cell; Equilibrium; Failure; Genes; Goals; Human; IL2RA gene; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immunity; Immunosuppressive Agents; Laboratories; Ligands; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Organ; Outcome; Outcome Study; Ovarian; PC3 cell line; Patients; Peptides; Phenotype; Physiologic pulse; Physiological; Play; Prevalence; Prostate; Prostatic Neoplasms; Receptor Signaling; Recruitment Activity; Regulation; Research; Research Personnel; Role; Sampling; Signal Pathway; Site; Specificity; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Tissues; Toll-like receptors; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Vaccination; Vaccines; base; cancer cell; cancer immunotherapy; cancer type; cytokine; established cell line; in vivo; insight; malignant breast neoplasm; melanoma; neoplastic cell; novel; programs; response; tumor; tumor growth

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.

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，但抑制有效癌症免疫治疗所需的免疫反应。我们最近证明了黑色素瘤和前列腺肿瘤浸润 T 细胞中存在抗原特异性 CD4+ Treg 细胞。这些观察结果至少可以部分解释为什么用癌症疫苗（包含 MHC I 类限制性肿瘤抗原或肽）引发强烈且持久的抗肿瘤反应的尝试基本上不成功。该项目的目标是研究前列腺癌中Treg细胞的存在是否会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超过50种前列腺肿瘤浸润T细胞(PTIL)。来自多个 PTIL 的 CD4+ 和 CD8+ Treg 细胞均显示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，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检验我们的假设，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 信号传导来调节或逆转。这些独特的前列腺 Treg 细胞系与几种新开发的技术一起，应该能够鉴定 CD4+ 和 CD8+ Treg 细胞的重要配体，从而允许对新概念进行更严格的测试 - 逆转 CD4+ 和/或 CD8+ Treg 的抑制功能细胞可能会提高癌症免疫疗法的有效性。为了检验我们的新概念和假设，我们提出了三个具体的研究目标：（1）根据表型标记、细胞因子谱和抑制机制来表征 PTIL 的不同子集； (2) 利用已建立的CD4+ Treg细胞系/克隆来鉴定编码这些细胞配体的基因，然后表征它们在调节Treg细胞活化中的作用； (3) 剖析 TLR 信号传导对 Treg 细胞的免疫抑制机制和调节，以获得检验我们的假设所需的关键信息，即逆转 CD4+ Treg 细胞的抑制功能将增强体内抗肿瘤免疫。这项为期5年的提案中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利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以及传染病和自身免疫性疾病开辟新的机会。