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

项目摘要/摘要 肿瘤特异性CD8 T细胞外周免疫耐受可能是产生高效抗肿瘤抗体的主要障碍 肿瘤免疫。最近的研究已经开始研究通过共刺激信号 分子可以充分增强免疫反应，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专注于 OX40(CD134)共刺激分子的连接机制 肿瘤坏死因子受体(TNFR)超家族，促进CD4和CD8T细胞的增殖， 分化和生存。重要的是，几项研究也表明OX40在 从荷瘤宿主肿瘤引流淋巴中分离T细胞及OX40 参与可以提高体内的抗肿瘤免疫能力。OX40介导的信号转导也被证明是 克服多肽诱导的CD4T细胞无能。最近，我们证明了OX40结扎可以 在体内恢复无能肿瘤反应性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，理解这些机制 调节肿瘤特异性无能的诱导可能导致新的治疗方法的发展 增强CD8 T细胞介导的抗肿瘤免疫的策略。为了实现这一建议，我们将 探讨常见的伽马链(GC)细胞因子IL-2和IL-4的调节机制 CD8 T细胞表面OX40受体的表达及其活化调控的分子机制 OX40启动子的基因。在AIM II中，我们将确定肿瘤诱导的分子机制 CD8 T细胞无能并验证联合抗OX40/GC细胞因子治疗可恢复的假说 无能CTL在荷瘤宿主中的作用AIM III试图测试抗OX40抗体的假设 治疗可促进小鼠内源性肿瘤特异性CD8T细胞的分化 并测试抗OX40治疗是否促进 肿瘤反应性CD8 T细胞在目前接受抗肿瘤药物治疗的癌症患者中的分化 激动剂抗OX40单抗在EACRI的I期临床试验中。总而言之，这些研究将 洞察OX40表达的调控机制，肿瘤的分子基础- 特异性CD8T细胞无能及抗OX40治疗能否增强内源性CD8T细胞 在荷瘤小鼠和癌症患者中的反应。

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.