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CD 8 T细胞外周耐受性可能是产生强效抗肿瘤免疫的主要障碍。最近的研究开始研究通过共刺激分子的信号传导是否可以充分增强免疫反应，以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一直专注于OX 40（CD 134）共刺激分子（肿瘤坏死因子受体（TNFR）超家族成员）的连接增强CD 4和CD 8 T细胞扩增、分化和存活的机制。重要的是，几项研究还表明，OX 40在从荷瘤宿主的肿瘤引流淋巴结分离的T细胞上表达，并且OX 40接合可以增强体内抗肿瘤免疫。还显示0X 40介导的信号传导克服肽诱导的CD 4 T细胞无反应性。最近，我们证明了OX 40连接可以在体内恢复无反应性肿瘤反应性CD 8 T细胞的功能。虽然抗OX 40治疗导致部分肿瘤消退，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导致开发新的治疗策略以增强CD 8 T细胞介导的抗肿瘤免疫。在本提案的目标I中，我们将研究常见伽马链（？c）细胞因子IL-2和IL-4调节CD 8 T细胞上的0X 40受体表达，包括调节0X 40启动子活化的分子机制。在目的二，我们将确定肿瘤诱导CD 8 T细胞无能的分子机制，并测试的假设，结合抗OX 40/？c细胞因子治疗可恢复荷瘤宿主无反应性CTL的功能。目的III旨在检验抗OX 40治疗可增强自发性前列腺癌小鼠中内源性肿瘤特异性CD 8 T细胞分化的假设，并检验抗OX 40治疗是否促进目前在EACRI I期临床试验中接受激动剂抗OX 40 mAb治疗的癌症患者中肿瘤反应性CD 8 T细胞的分化。总之，这些研究将提供对调节0X 40表达的机制、肿瘤特异性CD 8 T细胞无反应性的分子基础以及抗0X 40疗法是否可以增强荷瘤小鼠和癌症患者中的内源性CD 8 T细胞应答的深入了解。 公共卫生相关性：这些研究将测试抗0X 40抗体疗法是否可以增强CD 8 T细胞介导的抗肿瘤免疫并增强荷癌宿主的长期存活。沿着从正在进行的癌症患者中使用抗OX 40抗体的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，这些研究和临床试验有可能直接使癌症患者受益。