Ox40 mediated co-stimulation overcoming tumor-induced CD8 T cell peripheral toler

Ox40介导的共刺激克服肿瘤诱导的CD8 T细胞外周耐受

基本信息

批准号：
8470084
负责人：
William L Redmond
金额：
$ 22.7万
依托单位：
PROVIDENCE PORTLAND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470084
关键词：
Agonist Antibodies Antibody Therapy CD4 Positive T Lymphocytes CD8B1 gene Cancer Patient Cells Clinical Trials Data Development Family Family member Future Generations Immune response Interleukin 2 Receptor Gamma Interleukin-2 Interleukin-4 Laboratories Lead Ligation Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Molecular Profiling Mus Peptides Peripheral Phase I Clinical Trials Prostatic Neoplasms Regulation Signal Pathway Signal Transduction T cell anergy T cell response T-Lymphocyte Testing Tumor Immunity Tumor Necrosis Factor Receptor abstracting anergy base cytokine cytokine therapy functional restoration in vivo insight lymph nodes member novel therapeutics peripheral tolerance pre-clinical research promoter receptor expression research study tumor tumor microenvironment tumor necrosis factor receptor superfamily member 4

项目摘要

Project Summary/Abstract Tumor-specific CD8 T cell peripheral tolerance can be a major barrier to the generation of potent anti- tumor immunity. Recent studies have begun to examine whether signaling through co-stimulatory molecules can sufficiently boost the immune response to reverse tumor-specific tolerance and promote anti-tumor immunity. To this end, our laboratory and others have focused on the mechanisms through which ligation of the OX40 (CD134) co-stimulatory molecule, a member of tumor necrosis factor receptor (TNFR) super-family, augments CD4 and CD8 T cell expansion, differentiation, and survival. Importantly, several studies have also shown that OX40 is expressed on T cells isolated from the tumor-draining lymph nodes of tumor-bearing hosts and that OX40 engagement can boost anti-tumor immunity in vivo. OX40-mediated signaling has also been shown to overcome peptide-induced CD4 T cell anergy. Recently, we demonstrated that OX40 ligation could restore the function of anergic tumor-reactive CD8 T cells in vivo. Although anti-OX40 therapy led to partial tumor regression, the tumors ultimately recurred. Thus, understanding the mechanisms regulating the induction of tumor-specific anergy may lead to the development of new therapeutic strategies to enhance CD8 T cell-mediated anti-tumor immunity. In Aim I of this proposal, we will investigate the mechanisms by which the common gamma chain (gc) cytokines IL-2 and IL-4 regulate OX40 receptor expression on CD8 T cells including the molecular mechanisms regulating activation of the OX40 promoter. In Aim II, we will determine the molecular mechanisms by which tumors induce CD8 T cell anergy and test the hypothesis that combined anti-OX40/gc cytokine therapy can restore the function of anergic CTL in tumor-bearing hosts. Aim III seeks to test the hypothesis that anti-OX40 therapy can enhance the differentiation of endogenous tumor-specific CD8 T cells in mice with spontaneously arising prostate cancer and to test whether anti-OX40 therapy promotes the differentiation of tumor-reactive CD8 T cells in cancer patients that are currently being treated with an agonist anti-OX40 mAb in a phase I clinical trial at the EACRI. Taken together, these studies will provide insight into the mechanisms regulating OX40 expression, the molecular basis of tumor- specific CD8 T cell anergy, and whether anti-OX40 therapy can augment the endogenous CD8 T cell response in both tumor-bearing mice and cancer patients.

项目概要/摘要肿瘤特异性 CD8 T 细胞外周耐受可能是产生有效抗肿瘤药物的主要障碍。肿瘤免疫。最近的研究已经开始检验信号传导是否通过共刺激分子可以充分增强免疫反应，逆转肿瘤特异性耐受，促进抗肿瘤免疫力。为此，我们的实验室和其他机构一直致力于 OX40 (CD134) 共刺激分子的连接机制，该分子是肿瘤坏死因子受体 (TNFR) 超家族，增强 CD4 和 CD8 T 细胞扩增，分化和生存。重要的是，多项研究还表明 OX40 在从荷瘤宿主的肿瘤引流淋巴结中分离出的 T 细胞和 OX40 参与可以增强体内抗肿瘤免疫力。 OX40 介导的信号传导也已被证明克服肽诱导的 CD4 T 细胞无反应性。最近，我们证明 OX40 连接可以恢复体内无反应性肿瘤反应性 CD8 T 细胞的功能。尽管抗 OX40 治疗导致肿瘤部分消退，肿瘤最终复发。因此，了解机制调节肿瘤特异性无反应性的诱导可能会导致新治疗方法的开发增强CD8 T细胞介导的抗肿瘤免疫的策略。在本提案的目标 I 中，我们将研究常见伽玛链 (gc) 细胞因子 IL-2 和 IL-4 的调节机制 CD8 T 细胞上的 OX40 受体表达，包括调节激活的分子机制 OX40启动子的。在目标 II 中，我们将确定肿瘤诱导的分子机制 CD8 T 细胞无反应性并检验联合抗 OX40/gc 细胞因子治疗可以恢复的假设无能CTL在荷瘤宿主中的功能。目标 III 试图检验抗 OX40 抗体的假设治疗可以增强小鼠内源性肿瘤特异性 CD8 T 细胞的分化自发产生的前列腺癌并测试抗 OX40 疗法是否促进目前正在接受治疗的癌症患者中肿瘤反应性 CD8 T 细胞的分化 EACRI 的 I 期临床试验中的激动剂抗 OX40 mAb。总的来说，这些研究将提供对调节 OX40 表达的机制的深入了解，这是肿瘤的分子基础特异性 CD8 T 细胞无反应性，以及抗 OX40 治疗是否可以增强内源性 CD8 T 细胞荷瘤小鼠和癌症患者都有反应。