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

• 批准号: 8294589
• 负责人: William L Redmond
• 金额: $ 24.15万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294589
• 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 necrosis factor receptor superfamily member 4

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。