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: 7894245
• 负责人: William L Redmond
• 金额: $ 15.82万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894245
• 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; anergy; base; cytokine; cytokine therapy; functional restoration; in vivo; insight; lymph nodes; member; novel therapeutics; peripheral tolerance; pre-clinical research; promoter; public health relevance; receptor expression; research study; tumor; tumor necrosis factor receptor superfamily member 4

DESCRIPTION (provided by applicant): 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 (?c) 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/?c 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. PUBLIC HEALTH RELEVANCE: These studies will test whether anti-OX40 antibody therapy can enhance CD8 T cell-mediated anti- tumor immunity and enhance the long-term survival of cancer-bearing hosts. Along with the data obtained from an on-going Phase I clinical trial with an anti-OX40 antibody in cancer patients, the results generated in the proposed study will guide the development of future pre-clinical research studies and clinical trials with the potential to directly benefit cancer patients.

描述（由申请人提供）：肿瘤特异性CD8 T细胞外周耐受可能是产生有效抗肿瘤免疫的主要障碍。最近的研究已经开始研究通过共刺激分子发出的信号是否能够充分增强免疫反应，从而逆转肿瘤特异性耐受并促进抗肿瘤免疫。为此，我们的实验室和其他实验室重点研究了肿瘤坏死因子受体 (TNFR) 超家族成员 OX40 (CD134) 共刺激分子的连接增强 CD4 和 CD8 T 细胞扩增、分化和存活的机制。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的 T 细胞上表达，OX40 的参与可以增强体内抗肿瘤免疫力。 OX40 介导的信号传导也被证明可以克服肽诱导的 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疗法导致部分肿瘤消退，但肿瘤最终复发。因此，了解调节肿瘤特异性无反应性诱导的机制可能会导致开发新的治疗策略来增强 CD8 T 细胞介导的抗肿瘤免疫。在本提案的目标 I 中，我们将研究常见的伽马链 (?c) 细胞因子 IL-2 和 IL-4 调节 CD8 T 细胞上 OX40 受体表达的机制，包括调节 OX40 启动子激活的分子机制。在目标 II 中，我们将确定肿瘤诱导 CD8 T 细胞无反应性的分子机制，并测试联合抗 OX40/?c 细胞因子治疗可以恢复荷瘤宿主中无反应性 CTL 功能的假设。 Aim III 旨在测试抗 OX40 疗法可以增强自发性前列腺癌小鼠体内源性肿瘤特异性 CD8 T 细胞分化的假设，并测试抗 OX40 疗法是否可以促进目前正在 EACRI 进行的 I 期临床试验中接受激动剂抗 OX40 mAb 治疗的癌症患者的肿瘤反应性 CD8 T 细胞的分化。总而言之，这些研究将深入了解 OX40 表达的调节机制、肿瘤特异性 CD8 T 细胞无反应性的分子基础，以及抗 OX40 治疗是否可以增强荷瘤小鼠和癌症患者的内源性 CD8 T 细胞反应。 公共健康相关性：这些研究将测试抗 OX40 抗体治疗是否可以增强 CD8 T 细胞介导的抗肿瘤免疫并增强癌症宿主的长期生存。连同正在进行的癌症患者抗 OX40 抗体 I 期临床试验中获得的数据，拟议研究中产生的结果将指导未来临床前研究和临床试验的发展，有可能直接使癌症患者受益。