Characterizing and Regulating Tumor-induced Regulatory T Cells

表征和调节肿瘤诱导的调节性 T 细胞

基本信息

批准号：
7777819
负责人：
CHRISTIAN H POEHLEIN
金额：
$ 13.29万
依托单位：
PROVIDENCE PORTLAND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777819
关键词：
Address Adopted Affect Amphiregulin Animal Model Antigens Autoimmune Diseases CD81 gene Cancer Patient Cancer Vaccines Cell Line Cells Clinic Clinical Trials Development Diagnosis Disease Epidermal Growth Factor Receptor Frequencies Future Gene Expression Gene-Modified Generations Genes Granulocyte-Macrophage Colony-Stimulating Factor Histologic Homeostasis IL2RA gene Immune System Diseases Immune response Immune system Immunotherapy In Vitro Kinetics Ligands Lymphocyte Malignant Neoplasms Melanoma Cell Modality Modeling Mus Patients Phenotype Play Pre-Clinical Model Progressive Disease Property Prostaglandin Receptor Regulatory T-Lymphocyte Research Personnel Role Signal Transduction Spleen Study Section Survival Rate T cell response T-Cell Activation T-Lymphocyte Therapeutic Translations Treatment Efficacy Tumor Antigens Tumor Cell Line Tumor Immunity Tumor Markers Vaccinated Vaccines base cancer therapy design improved in vivo innovation lymph nodes melanoma mouse model novel novel marker prevent programs receptor reconstitution response statistics therapeutic development tumor

项目摘要

DESCRIPTION (provided by applicant): Classic treatments for cancer have been refined and overall survival rates have improved, but better treatments are needed! T cell-based immunotherapy strategies have shown to be an effective therapeutic modality in animal models, however their translation into the clinic, with some notable exceptions, has been disappointing. We hypothesize that immunotherapy strategies fail because patients with cancer have a compromised immune system blocking an effective immune response against tumor antigens. It is becoming increasingly clear that regulatory T cells (Treg) play a critical role in limiting the development of therapeutic anti-tumor responses in preclinical models; and likely play the same role in cancer patients. Our overall hypothesis is that it is possible to eliminate the tumor-induced Treg (iTreg) that limit anti-tumor immune responses without deleting the natural Treg (nTreg) that prevent auto immune disease. Thus, it is critical to develop strategies that can manipulate regulatory T cells induced by cancer, so that vaccines can induce a strong tumor-specific T cell response. We have made progress in increasing the frequency and therapeutic efficacy of tumor-specific effector T cells generated in reconstituted, lymphopenic mice, exploiting homeostasis-driven proliferation. However, when reconstitution used B16BL6-D5 (D5) tumor-bearing mice (TBM) spleen cells, anti-tumor function was lost. Preliminary studies document, that D5 TBM develop CD4+CD25+ tumor-induced regulatory T cells (iTreg) that inhibit the generation of tumor-specific T cells. Further, depletion of CD25+ Treg cells prior to reconstitution successfully restored priming, and gene expression analysis of iTreg cells identified novel markers that can be exploited to deplete iTreg and recover the ability to generate therapeutic T cells in RLM. Some of these genes, which have not previously been associated with regulatory T cells, are up-regulated by iTreg and have signaling properties. This proposal will characterize expression of these novel molecules, investigate their role in the development and/or function of iTreg and explore their use in innovative strategies to increase the priming and therapeutic efficacy of cancer vaccines. Relevance: Results from this proposal will directly influence the translation and advance the design of T cell-based immunotherapy strategies to find a better treatment for patients with progressive disease in current and future clinical trials adopting the findings of these studies to enhance patient therapy.

描述（由申请人提供）：癌症的经典治疗方法已得到完善，总体存活率有所提高，但需要更好的治疗方法！基于T细胞的免疫疗法策略已证明是动物模型中的一种有效的治疗方式，但是它们转化为诊所，除了一些明显的例外，令人失望。我们假设免疫疗法策略失败了，因为癌症患者的免疫系统受损，可阻止针对肿瘤抗原的有效免疫反应。越来越清楚的是，调节性T细胞（TREG）在限制临床前模型中治疗性抗肿瘤反应的发展中起着关键作用。并且可能在癌症患者中起着相同的作用。我们的总体假设是，可以消除肿瘤诱导的TREG（ITREG），从而限制抗肿瘤免疫反应而不会删除预防自身免疫疾病的天然Treg（NTREG）。因此，制定可以操纵癌症诱导的调节性T细胞的策略至关重要，从而使疫苗可以诱导强烈的肿瘤特异性T细胞反应。我们在增加了在重构的，淋巴细胞减少小鼠中产生的肿瘤特异性效应T细胞的频率和治疗功效方面取得了进展，从而利用了体内平衡的增殖。但是，当重建使用B16BL6-D5（D5）肿瘤小鼠（TBM）脾细胞时，抗肿瘤功能就会丢失。初步研究证明，D5 TBM会发展CD4+ CD25+肿瘤诱导的调节性T细胞（ITREG），抑制肿瘤特异性T细胞的产生。此外，在重新建立之前，CD25+ Treg细胞的耗竭成功地恢复了启动，ITREG细胞的基因表达分析鉴定出可以利用的新标记物来耗尽ITREG并恢复RLM中产生治疗性T细胞的能力。这些基因以前尚未与调节性T细胞相关的基因，由ITREG上调并具有信号传导特性。该建议将表征这些新分子的表达，研究它们在ITREG的发展和/或功能中的作用，并探索它们在创新策略中的使用，以提高癌症疫苗的启动和治疗功效。相关性：该提案的结果将直接影响基于T细胞的免疫疗法策略的翻译并推进设计，以在当前和将来的临床试验中为患有进行性疾病的患者找到更好的治疗，从而采用了这些研究的结果来增强患者治疗。