THE ROLE AND MECHANISMS OF CD4+ T CELLS IN ANTITUMOR IMMUNITY

CD4 T细胞在抗肿瘤免疫中的作用和机制

• 批准号: 8217341
• 负责人: Rongfu Wang
• 金额: $ 26.92万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8217341
• 关键词: Antigens; Antitumor Response; B-Lymphocytes; Biopsy; Blood specimen; Breast Melanoma; Burkitt Lymphoma; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Center; Cancer Patient; Cancer Vaccines; Cell Line; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Trials; Complement; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Disease; Distant; Dose; Enrollment; Etiology; Generations; Geographic Distribution; Goals; Head and Neck Cancer; Hodgkin Disease; Human; Human Herpesvirus 4; IL2RA gene; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Laboratories; Ligands; Link; Lung; Lymphoproliferative Disorders; MHC Class II Genes; Malignant Neoplasms; Mediating; Methods; Molecular; Mus; Nasopharynx Carcinoma; Natural Immunity; Nonmetastatic; Oligonucleotides; Ovarian; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Play; Poly G; Population; Prevalence; Proteins; RNA Interference; Radiation therapy; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Role; Schedule; Signal Pathway; Signal Transduction; Solid Neoplasm; Staging; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; TLR8 gene; Testing; Therapeutic; Therapeutic Effect; Toll-like receptors; Transgenic Mice; Transplantation; Tropism; Tumor Bank; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Vaccination; Work; adaptive immunity; base; cancer immunotherapy; cancer type; chemotherapy; cytokine; design; follow-up; gammaherpesvirus; human TLR8 protein; improved; in vivo; in vivo Model; insight; interest; macrophage; mouse model; neoplastic cell; novel; novel strategies; outcome forecast; peripheral blood; programs; response; standard care; success; tumor

One of the major impediments to effective immunotherapy for cancer has been the influence of negative mmunoregulatory mechanisms on otherwise potent immune responses, including CD4+ CD25+ negativeregulatory T cells (Tregs) contained in the tumor-infiltrating lymphocyte population. Investigators in Project 2 (R. Wang, Leader) recently shifted their research to this problem after finding that some of their newly discovered EBV-EBNA1-derived T-cell epitopes could stimulate both CD4+ effector and Treg cells, the latter having the capacity to suppress na'i've T-cell proliferation and immune responses. Further work to exploit this observation showed that TLR8 ligands (Poly-G oligonucleotides) can directly reverse the suppressive function of Treg cells. Consequently, Wang and his group have postulated that EBV-positive Hodgkin disease (HD) and nasopharyngeal carcinoma (NPC), tumors of wide interest to this program project, are enriched with Treg cells whose suppressive function could inhibit the therapeutic effect of T-cell immunotherapy. They will pursue this concept in the current proposal, using both in vitro and in vivo models. In Aim 1 they intend to establish the subsets and prevalence of Treg cells in clinical tumor samples and blood from patients with HD or NPC and then elucidate their suppressive function and mechanisms in human tumor mouse models. To link TLR8 signaling to Treg suppressive function, they propose in Aim 2 to exploit RNA interference (RNAi)-mediated knockdown and TLR8 transgenic mice to determine the signaling pathways or, at least, the key molecules controlling Treg cell function. Ultimately, in Aim 3, they will test three novel strategies in transgenic mice that may improve antitumor responses to cancer vaccines and CTL-based immunotherapy for EBV-positive tumors: 1) use of TLR8 ligands to block the suppressive function of Treg cells; 2) as in 1 except the ligands will be covalently linked to MHC class II- and l-restricted peptides/proteins to enhance CD4+ and CD8+ T-cell responses; and 3) a combination of 1 and 2. The results of this research will be of considerable interest to investigators in Projects 1, 3 and 4, as the availability of a method to suppress Treg cell function in the tumor microenvironment would nicely complement efforts to render EBV-positive or negative tumor cells resistant to the direct inhibitory effects of cytokines and other factors that can impede the antitumor activity of CTLs. Lay summary - Among the many obstacles to effective immunotherapy for cancer, the negative activity of T cells with the ability to suppress immune responses has been the most difficult to overcome. This group of investigators has identified an agent that can eliminate this barrier in the laboratory and now propose to find the best way to use it to neutralize unwanted T cells in the body.

癌症有效免疫治疗的主要障碍之一是负性免疫缺陷的影响。 免疫调节机制，包括CD 4 + CD 25+负调节 肿瘤浸润性淋巴细胞群中所含的T细胞（TcB）。项目2中的研究人员 （R.王，领导）最近将他们的研究转移到这个问题后，发现他们的一些新的， 发现EBV-EBNA 1衍生的T细胞表位可以刺激CD 4+效应细胞和Treg细胞， 后者具有抑制天然T细胞增殖和免疫应答的能力。进一步努力 利用这一观察结果表明，TLR 8配体（Poly-G寡核苷酸）可以直接逆转 Treg细胞的抑制功能。因此，Wang和他的团队假设EBV阳性 何杰金氏病（HD）和鼻咽癌（NPC），本计划广泛关注的肿瘤 项目，富含Treg细胞，其抑制功能可以抑制T细胞的治疗效果， 免疫疗法他们将在目前的提案中使用体外和体内模型来追求这一概念。 在目标1中，他们打算建立临床肿瘤样本中Treg细胞的亚群和患病率， 从HD或NPC患者的血液中提取，然后阐明它们在人类中的抑制功能和机制。 肿瘤小鼠模型。为了将TLR 8信号传导与Treg抑制功能联系起来，他们在Aim 2中提出利用 RNA干扰（RNAi）介导的敲低和TLR 8转基因小鼠，以确定信号转导 途径，或者至少是控制Treg细胞功能的关键分子。最终，在目标3中，他们将测试 转基因小鼠中的三种新策略可能改善对癌症疫苗的抗肿瘤反应， 用于EBV阳性肿瘤的基于CTL的免疫疗法：1）使用TLR 8配体来阻断抑制性免疫应答， Treg细胞的功能; 2）如1中所述，除了配体将共价连接至MHC II类和I类限制性 增强CD 4+和CD 8 + T细胞应答的肽/蛋白;和3）1和2的组合。的 这项研究的结果将是相当感兴趣的研究人员在项目1，3和4，因为 一种抑制肿瘤微环境中Treg细胞功能的方法的可用性将很好地 补充努力，使EBV阳性或阴性肿瘤细胞对以下物质的直接抑制作用具有抗性： 细胞因子和其他可阻碍CTL抗肿瘤活性的因子。摘要-在 许多障碍，有效的免疫治疗癌症，负活性的T细胞的能力， 抑制免疫反应是最难克服的。这组调查人员已经 我在实验室中确定了一种可以消除这种障碍的药剂，现在我提出要找到最好的方法， 用来中和体内多余的T细胞