Correction of dendritic cells defects in cancer

描述（由申请人提供）：尽管在临床试验中测试的免疫策略具有很高的前景，但尚未为大多数患者带来切实的益处。许多临床试验已经证明了针对肿瘤特异性抗原的免疫应答的成功产生。然而，这些反应与大多数患者的临床反应无关。越来越清楚的是，限制免疫治疗有效性的主要因素之一是免疫抑制性肿瘤微环境，它阻止细胞毒性T细胞（CTL）识别和消除肿瘤。Parent Grant致力于了解髓源性抑制细胞（MDSC）诱导的T细胞缺陷的机制。在实现该项目目标的过程中，我们发现MDSC介导的T细胞耐受性的主要机制之一是由MDSC产生的活性氧（ROS）和氮（RNS）物质的增加引起的TCR的翻译后修饰。在今次修订中，我们建议扩大家长津贴的范围。基于我们新的初步数据，我们提出过亚硝酸根和其他ROS在肿瘤微环境中通过浸润骨髓细胞或肿瘤细胞产生的影响比仅仅对T细胞的影响要广泛得多。我们认为，过氧亚硝酸盐和ROS导致修改的MHC I类分子表达的肿瘤细胞和/或肿瘤特异性肽提出的这些MHC I类分子。这将使得对肿瘤抗原衍生肽特异性的CTL不能识别和消除肿瘤细胞。因此，即使癌症免疫治疗导致产生有效的抗原特异性CTL，或者如果这些CTL在体外产生，然后过继转移到患者，MHC I类的翻译后修饰也会抵消任何可能的抗肿瘤作用。由于髓样细胞浸润和过氧亚硝酸盐产生的水平因患者而异，这可能是用过继转移T细胞或疫苗治疗患者的可变结果的原因。在拟议的研究中，我们计划通过实验来验证这一假设。我们还将测试通过采用新化合物RTA 402逆转过氧亚硝酸盐的影响的可能性，RTA 402已被证明在阻断活性氧和减少过氧亚硝酸盐的产生方面具有高水平的活性。我们提出以下具体目标：具体目标1。探讨肺癌动物模型中活性氧和活性氮的过度生成与肿瘤逃逸的关系。具体目标2。在肺癌的临床前模型中确定新型治疗化合物逆转过氧亚硝酸盐诱导的肿瘤从细胞毒性T细胞逃逸的能力。 公共卫生相关性：拟议的研究将探讨与肿瘤组织中过氧亚硝酸盐产生增加相关的肿瘤逃逸的新机制。我们将测试新的假设，即细胞毒性T淋巴细胞不能识别和消除肿瘤细胞部分是由过氧亚硝酸盐诱导的修饰的MHC I类和/或肽表位的肿瘤细胞表面上。我们将研究这种现象的机制，并测试几种治疗方法来消除这种影响，以提高癌症免疫治疗的效果。

DESCRIPTION (provided by applicant): Despite high promise the immunotherapeutic strategies that have been tested in clinical trials have not yet delivered tangible benefits to most patients. Numerous clinical trials have demonstrated successful generation of immune responses against tumor-specific antigens. However, these responses have not been associated with clinical responses in most patients. It has become increasingly clear that one of the major factors that limit the effectiveness of immunotherapy is the immunosuppressive tumor microenvironment, which prevents cytotoxic T cells (CTL) from recognizing and eliminating tumor. Parent grant is focused to understanding the mechanisms of T-cell defects induced by myeloid-derived suppressor cells (MDSC). In a course of implementation of the goals of the project we found that one of the major mechanisms of MDSC mediated T-cell tolerance was a posttranslational modification of TCR caused by increased production of reactive oxygen (ROS) and nitrogen (RNS) species by MDSC. In current revision we propose to expand the scope of the parent grant. Based on our new preliminary data we propose that effect of peroxynitrite and other ROS produced in tumor microenvironment by infiltrating myeloid cells or tumor cells is much broader than just effect on T cells. We suggest that peroxynitrite and ROS cause modification of MHC class I molecules expressed on tumor cells and/or tumor-specific peptides presented by those MHC class I molecules. This would make CTLs specific for tumor antigen derived peptides unable to recognize and eliminate tumor cells. Thus, even if cancer immunotherapy results in the generation of potent antigen-specific CTLs or if these CTLs are generated in vitro and then adoptively transferred to patients, post-translational modification of MHC class I would negate any possible antitumor effect. Since the level of myeloid cell infiltration and peroxynitrite production varies from patient to patient this may account for variable results of patients' treatment with adoptive transfer of T cells or vaccines. In the proposed study we plan to experimentally test this hypothesis. We will also test the possibility of reversing the effect of peroxynitrite by employing the novel compound RTA 402, which has been demonstrated to have a high level of activity in blocking reactive oxygen species and decreasing peroxynitrite production. We propose the following specific aims: Specific aim 1. To identify the mechanism of tumor escape associated with hyperproduction of reactive oxygen and nitrogen species in animal models of lung cancer. Specific aim 2. To determine in preclinical models of lung cancer the ability of novel therapeutic compounds to reverse the peroxynitrite-inducible tumor escape from cytotoxic T cells. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism of tumor escape associated with increased production of peroxynitrite in tumor tissues. We will test novel hypothesis that inability of cytotoxic T lymphocytes to recognize and eliminate tumor cells was caused in part by peroxynitrite inducible modifications of MHC class I and/or peptide epitopes on the surface of tumor cells. We will investigate the mechanism of this phenomenon and test several therapeutic approaches to eliminate this effect with goal to enhance the effect of cancer immunotherapy.