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

描述(申请人提供)：肿瘤特异性CD8 T细胞外周耐受可能是产生强大的抗肿瘤免疫的主要障碍。最近的研究已经开始检验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，促进抗肿瘤免疫。为此，我们的实验室和其他实验室致力于研究肿瘤坏死因子受体(TNFR)超家族成员OX40(CD134)共刺激分子通过连接促进CD4和CD8T细胞的增殖、分化和存活的机制。重要的是，一些研究还表明，OX40表达于从荷瘤宿主的肿瘤引流淋巴结分离出来的T细胞上，并且OX40的参与可以增强体内的抗肿瘤免疫。OX40介导的信号也被证明可以克服多肽诱导的CD4T细胞无能。最近，我们在体内证明了OX40结扎可以恢复无能的肿瘤反应性CD8 T细胞的功能。虽然抗OX40治疗导致肿瘤部分消退，但肿瘤最终复发。因此，了解肿瘤特异性无能诱导的调控机制可能有助于开发新的治疗策略，以增强CD8T细胞介导的抗肿瘤免疫。本研究的目的一是探讨常见的γ链细胞因子IL-2和IL-4调节CD8T细胞表面OX40受体表达的机制，包括调节OX40启动子激活的分子机制。在AIM II中，我们将确定肿瘤诱导CD8T细胞无能的分子机制，并验证联合抗OX40/？C细胞因子治疗可以恢复荷瘤宿主无能CTL功能的假设。目的III旨在验证抗OX40治疗可以促进自发前列腺癌小鼠内源性肿瘤特异性CD8 T细胞分化的假设，并在EACRI的I期临床试验中测试抗OX40治疗是否促进癌症患者肿瘤反应性CD8 T细胞的分化。综上所述，这些研究将深入了解OX40表达的调控机制，肿瘤特异性CD8 T细胞无能的分子基础，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。 公共卫生相关性：这些研究将测试抗OX40抗体治疗是否可以增强CD8T细胞介导的抗肿瘤免疫，并提高携带癌症的宿主的长期存活率。连同正在进行的癌症患者抗OX40抗体第一阶段临床试验获得的数据，拟议研究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。

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.